Drug releasing coatings for medical devices

ABSTRACT

The invention relates to a medical device for delivering a therapeutic agent to a tissue. The medical device has a layer overlying the exterior surface of the medical device. The layer contains a therapeutic agent and an additive. In certain embodiments, the additive has a hydrophilic part and a drug affinity part, wherein the drug affinity part is at least one of a hydrophobic part, a part that has an affinity to the therapeutic agent by hydrogen bonding, and a part that has an affinity to the therapeutic agent by van der Waals interactions. In embodiments, the additive is water-soluble. In further embodiments, the additive is at least one of a surfactant and a chemical compound, and the chemical compound has a molecular weight of from 80 to 750 or has more than four hydroxyl groups.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 12/121,986, filed May 16,2008, which is a continuation-in-part of application Ser. No.11/942,452, filed Nov. 19, 2007, which claims the benefit of priority ofU.S. Provisional Application No. 60/860,084, filed on Nov. 20, 2006,U.S. Provisional Application No. 60/880,742, filed Jan. 17, 2007, U.S.Provisional Application No. 60/897,427, filed on Jan. 25, 2007, U.S.Provisional Application No. 60/903,529 filed on Feb. 26, 2007, U.S.Provisional Application No. 60/904,473 filed Mar. 2, 2007, U.S.Provisional Application No. 60/926,850 filed Apr. 30, 2007, U.S.Provisional Application No. 60/981,380 filed Oct. 19, 2007, and U.S.Provisional Application No. 60/981,384 filed Oct. 19, 2007, thedisclosures of all of which are incorporated by reference herein.

FIELD OF THE INVENTION

Embodiments of the present invention relate to coated medical devices,and particularly to coated balloon catheters, and their use for rapidlydelivering a therapeutic agent to particular tissue or body lumen, fortreatment of disease and particularly for reducing stenosis and latelumen loss of a body lumen. Embodiments of the present invention alsorelate to methods of manufacturing these medical devices, the coatingsprovided on these medical devices, the solutions for making thosecoatings, and methods for treating a body lumen such as the vasculature,including particularly arterial vasculature, for example, using thesecoated medical devices.

BACKGROUND OF THE INVENTION

It has become increasingly common to treat a variety of medicalconditions by introducing a medical device into the vascular system orother lumen within a human or veterinary patient such as the esophagus,trachea, colon, biliary tract, or urinary tract. For example, medicaldevices used for the treatment of vascular disease include stents,catheters, balloon catheters, guide wires, cannulas and the like. Whilethese medical devices initially appear successful, the benefits areoften compromised by the occurrence of complications, such as latethrombosis, or recurrence of disease, such as stenosis (restenosis),after such treatment.

Restenosis, for example, involves a physiological response to thevascular injury caused by angioplasty. Over time, de-endotheliaziationand injury to smooth muscle cells results in thrombus deposition,leukocyte and macrophage infiltration, smooth muscle cellproliferation/migration, fibrosis and extracellular matrix deposition.Inflammation plays a pivotal role linking early vascular injury to theeventual consequence of neointimal growth and lumen compromise. Inballoon-injured arteries, leukocyte recruitment is confined to earlyneutrophil infiltration, while in stented arteries, early neutrophilrecruitment is followed by prolonged macrophage accumulation. Thewidespread use of coronary stents has altered the vascular response toinjury by causing a more intense and prolonged inflammatory state, dueto chronic irritation from the implanted foreign body, and in the caseof drug eluting stents (DES), from insufficient biocompatibility of thepolymer coating.

Over the past several years, numerous local drug delivery systems havebeen developed for the treatment and/or the prevention of restenosisafter balloon angioplasty or stenting. Examples include local drugdelivery catheters, delivery balloon catheters, and polymeric drugcoated stents. Given that many diseases affect a specific local site ororgan within the body, it is advantageous to preferentially treat onlythe affected area. This avoids high systemic drug levels, which mayresult in adverse side effects, and concentrates therapeutic agents inthe local area where they are needed. By treating just the diseasedtissue, the total quantity of drug used may be significantly reduced.Moreover, local drug delivery may allow for the use of certain effectivetherapeutic agents, which have previously been considered too toxic ornon-specific to use systemically.

One example of a local delivery system is a drug eluting stent (DES).The stent is coated with a polymer into which drug is impregnated. Whenthe stent is inserted into a blood vessel, the polymer degrades and thedrug is slowly released. The slow release of the drug, which takes placeover a period of weeks to months, has been reported as one of the mainadvantages of using DES. However, while slow release may be advantageousin the case where a foreign body, such as a stent, is deployed, which isa source of chronic irritation and inflammation, if a foreign body isnot implanted it is instead advantageous to rapidly deliver drug to thevascular tissue at the time of treatment to inhibit inflammation andcellular proliferation following acute injury. Thus, a considerabledisadvantage of a DES, or any other implanted medical device designedfor sustained release of a drug, is that the drug is incapable of beingrapidly released into the vessel.

Additionally, while drug-eluting stents were initially shown to be aneffective technique for reducing and preventing restenosis, recentlytheir efficacy and safety have been questioned. A life-threateningcomplication of the technology, late thrombosis, has emerged as a majorconcern. Drug eluting stents cause substantial impairment of arterialhealing, characterized by a lack of complete re-endothelialization and apersistence of fibrin when compared to bare metal stents (BMS), which isunderstood to be the underlying cause of late DES thrombosis. Concernshave also been raised that the polymeric matrix on the stent in whichthe anti-proliferative drug is embedded might exacerbate inflammationand thrombosis, since the polymers used are not sufficientlybiocompatible. These polymeric systems are designed to facilitatelong-term sustained release of drug over a period of days, months, oryears, not over a period of seconds or minutes. These polymeric drugcoatings of medical devices do not release the polymer, which remains onthe device even after drug is released. Even if biodegradable polymersare used, polymer and drug are not released at the same time. Rapidrelease of drug, an intent of embodiments of the present invention, fromthese polymeric systems is not possible. Thus, combining a therapeuticagent with a polymer in a medical device coating may have significantdisadvantages.

Another important limitation of the DES is that the water insolubledrugs are not evenly distributed in the polymeric matrix of the coating.Furthermore, drug and polymer are concentrated on the struts of thestent, but not in gaps between the struts. The non-uniform distributionof drug causes non-uniform drug release to the tissue of the vesselwalls. This may cause tissue damage and thrombosis in areas exposed toexcess drug and hyperplasia and restenosis areas that are undertreated.Thus, there is a need to improve the uniformity of drug delivery totarget tissues by improving drug solubility in coatings of medicaldevices by increasing the drug's compatibility with carriers in thecoatings, such as a polymeric matrix, thereby eliminating or reducingthe size of drug crystal particles in the polymeric matrix or othercoating to create a uniform drug distribution in the drug coating on themedical device.

Yet another important limitation of the DES is that only a limitedamount of an active agent can be loaded into the relatively smallsurface area of the stent.

Non-stent based local delivery systems, such as balloon catheters, havealso been effective in the treatment and prevention of restenosis. Theballoon is coated with an active agent, and when the blood vessel isdilated, the balloon is pressed against the vessel wall to deliver theactive agent. Thus, when balloon catheters are used, it is advantageousfor the drug in the coating to be rapidly released and absorbed by bloodvessel tissues. Any component of the coating that inhibits rapidrelease, such as a lipid or polymer or an encapsulating particle, isnecessarily disadvantageous to the intended use of the balloon catheter,which is inflated for a very brief period of time and then removed fromthe body.

Hydrophilic drugs, such as heparin, have been reported to be deliverableby polymeric hydrogel coated balloon catheters. However, a polymerichydrogel coating can not effectively deliver water insoluble drugs (suchas paclitaxel and rapamycin), because they can not mix with the hydrogelcoating. Furthermore, as drug is released, the cross-linked polymerichydrogel remains on the balloon after drug is released. The iodinecontrast agent iopromide has been used with paclitaxel to coat ballooncatheters and has some success in treatment of restenosis. It wasreported that contrast agent improves adhesion of paclitaxel to theballoon surface. However, iodinated contrast agents suffer from severalwell known disadvantages. When used for diagnostic procedures, they mayhave complication rates of 5-30%. These agents are associated with therisk of bradycardia, ventricular arrthymia, hypotension, heart block,sinus arrest, sinus tachycardia, and fibrillation. Iodine contrastagents may also induce renal failure, and as a result there aresignificant efforts to remove these contrast agents from the vascularsystem after diagnostic procedures.

In addition, the Food and Drug Administration (FDA) issued a secondpublic health advisory in 2006 about a serious late adverse reaction tocontrast agents known as Nephrogenic Systemic Fibrosis or NephrogenicFibrosing Dermopathy. Given the breadth of adverse events associatedwith intravascular delivery of contrast agents, improved medical devicesare needed with coatings that do not inherently dose a patient withadditional contrast agent in order to deliver a desired therapeuticagent.

Iodinated X-ray contrast agents are large hydrophilic sphericalmolecules. They are characterized by an extracellular distribution andrapid glomerular filtration and renal excretion. They are unable tocross membrane lipid bilayers to enter cells of the vasculature becausethey are large, polar, hydrophilic molecules. They are therefore notoptimally effective at carrying hydrophobic drugs such as paclitaxelinto cells, and the percent of paclitaxel reported to be taken up byvascular tissue after deployment of these devices is only 5-20%. Inaddition, the compatability or miscibility of paclitaxel and iopromideis not good, and the integrity and uniformity of the coating is poor.Particles from the coating easily flake off and are lost duringhandling. These deficiencies adversely affect the amount and uniformityof drug delivered to target tissue. Improved coatings are thereforeneeded, coatings that not only avoid unnecessary doses of contrast, butthat also maintain integrity during handling and more effectively anduniformly deliver drug and facilitate its absorption by tissue.

Alternatively, balloon catheters are reported to have been coated withhydrophobic therapeutic agents that have been mixed with oils or lipidsor encapsulated in particles such as liposomes or polymers. All of thesedrug delivery formulations have significant disadvantages. Unlikehydrophilic contrast agents, oils and lipids mix well withwater-insoluble drugs such as paclitaxel or rapamycin, but the particlesizes of oils used for solubilizing the therapeutic agents arerelatively unstable, ranging in a broad particle size distribution fromseveral hundred nanometers to several microns in diameter.

Loading capacity of conventional micelles is low. Another disadvantageof oil-based liposome formulations is the dependence of drug absorptionon the rate and extent of lipolysis. Lipolysis of oil-basedtriglycerides is difficult and dependent upon many factors, andtriglycerides must be digested and drug released in order to be absorbedby diseased tissue. The amount of hydrophobic drug delivered to tissuesby these agents will be low, because liposomes and micelles cannotefficiently release hydrophobic drug, which they carry away before itcan be absorbed by tissues. Oils and lipids are therefore not effectiveat rapidly and efficiently facilitating tissue uptake of drug during avery brief device deployment time, and no report has shown these typesof coatings to be effective. The ratio of drug to lipid in theseformulations is typically 0.2-0.3, because the drugs are encapsulated inthe particles, miscelles, or liposomes, which requires a significantlyhigher concentration of lipid than drug. These technologies involveforming the drug/lipid particles first and then coating medical deviceswith the prepared particles. There are several reports showing that drugrelease from these oil/lipid formulations occurs in the range of days toweeks or months. This property is not desirable for situations wheredrug release takes place in the range of seconds to minutes. Thus, thetechnology for oil/lipid formulation needs to be improved significantlyin order to be useful in such situations.

Drug that is encapsulated in polymeric particles may take even longer todiffuse from the coating (the reported range is months to years) andwill have further difficulty permeating target tissues rapidly.Microspheres formed with polymeric materials, such as polyesters, whenused to encapsulate water insoluble drugs, are unable to release thedrug until the polymeric material is degraded. Thus, these polymericmicrospheres are useful for sustained release of drug over a long periodof time, but cannot rapidly release drug and facilitate tissue uptake.

Combining drugs and medical devices is a complicated area of technology.It involves the usual formulation challenges, such as those of oral orinjectable pharmaceuticals, together with the added challenge ofmaintaining drug adherence to the medical device until it reaches thetarget site and subsequently delivering the drug to the target tissueswith the desired release and absorption kinetics. Drug coatings ofmedical devices must also have properties such that they do not crackupon expansion and contraction of the device, for example, of a ballooncatheter or a stent. Furthermore, coatings must not impair functionalperformance such as burst pressure and compliance of balloons or theradial strength of self- or balloon-expanded stents. The coatingthickness must also be kept to a minimum, since a thick coating wouldincrease the medical device's profile and lead to poor trackability anddeliverability. These coatings generally contain almost no liquidchemicals, which typically are often used to stabilize drugs. Thus,formulations that are effective with pills or injectables might not workat all with coatings of medical device. If the drug releases from thedevice too easily, it may be lost during device delivery before it canbe deployed at the target site, or it may burst off the device duringthe initial phase of inflation and wash away before being pressed intocontact with target tissue of a body lumen wall. If the drug adheres toostrongly, the device may be withdrawn before the drug can be releasedand absorbed by tissues at the target tissues.

Thus, there is still a need to develop highly specialized coatings formedical devices that can rapidly deliver therapeutic agents, drugs, orbioactive materials directly into a localized tissue area during orfollowing a medical procedure, so as to treat or prevent vascular andnonvascular diseases such as restenosis. The device should quicklyrelease the therapeutic agent in an effective and efficient manner atthe desired target location, where the therapeutic agent should rapidlypermeate the target tissue to treat disease, for example, to relievestenosis and prevent restenosis and late lumen loss of a body lumen.

SUMMARY OF THE INVENTION

The present inventor has found that coating the exterior surface of amedical device, and particularly of a balloon catheter or a stent, forexample, with a layer comprising a therapeutic agent and an additivethat has both a hydrophilic part and a drug affinity part is useful insolving the problems associated with the coatings discussed above. Thedrug affinity part is a hydrophobic part and/or has an affinity to thetherapeutic agent by hydrogen bonding and/or van der Waals interactions.Surprisingly, the present inventor has found that the at least oneadditive according to embodiments of the present invention, whichcomprises a hydrophilic part and a drug affinity part, in combinationwith a therapeutic agent, forms an effective drug delivery coating on amedical device without the use of oils and lipids, thereby avoiding thelipolysis dependence and other disadvantages of conventional oil-basedcoating formulations. Moreover, the additives according to embodimentsof the present invention facilitate rapid drug elution and superiorpermeation of drug into tissues at a disease site. Thus, coatingsaccording to embodiments of the present invention provide an enhancedrate and/or extent of absorption of the hydrophobic therapeutic agent indiseased tissues of the vasculature or other body lumen. In embodimentsof the present invention, the coated device delivers therapeutic agentto tissue during a very brief deployment time of less than 2 minutes andreduces stenosis and late lumen loss of a body lumen.

In one embodiment, the present invention relates to a medical device fordelivering a therapeutic agent to a tissue, the device comprising alayer overlying an exterior surface of the medical device. The deviceincludes one of a balloon catheter, a perfusion balloon catheter, aninfusion catheter such as distal perforated drug infusion tube, aperforated balloon, spaced double balloon, porous balloon, and weepingballoon, a cutting balloon catheter, a scoring balloon catheter, a lasercatheter, an atherectomy device, a debulking catheter, a stent, afilter, a stent graft, a covered stent, a patch, a wire, and a valve.Further, the tissue includes tissue of one of coronary vasculature,peripheral vasculature, cerebral vasculature, esophagus, airways, sinus,trachea, colon, biliary tract, urinary tract, prostate, and brainpassages.

In one embodiment of the medical device, the coating layer overlying thesurface of a medical device comprises a therapeutic agent and anadditive, wherein the additive comprises a hydrophilic part and a drugaffinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive iswater-soluble, wherein the additive is at least one of a surfactant anda chemical compound, and wherein the chemical compound has a molecularweight of from 80 to 750.

In one embodiment, the coating layer overlying the exterior surface ofthe medical device comprises a therapeutic agent and an additive,wherein the additive comprises a hydrophilic part and a drug affinitypart, wherein the drug affinity part is at least one of a hydrophobicpart, a part that has an affinity to the therapeutic agent by hydrogenbonding, and a part that has an affinity to the therapeutic agent by vander Waals interactions, wherein the additive is at least one of asurfactant and a chemical compound, and wherein the chemical compoundhas more than four hydroxyl groups. In one embodiment, the chemicalcompound having more than four hydroxyl groups has a melting point of120° C. or less, and the chemical compound is an alcohol or an ester.

In one embodiment, the layer overlying the exterior surface of themedical device consists essentially of the therapeutic agent and theadditive. In one embodiment, the layer overlying the exterior surface ofthe medical device does not include an iodine covalent bonded contrastagent. In one embodiment, the chemical compound has one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In oneembodiment, the chemical compound is chosen from amino alcohols,hydroxyl carboxylic acid, ester, anhydrides, hydroxyl ketone, hydroxyllactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide,ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic acids, esters, salts,vitamins, combinations of amino alcohol and organic acid, and theirsubstituted molecules. In another embodiment, the surfactant is chosenfrom ionic, nonionic, aliphatic, and aromatic surfactants, PEG fattyesters, PEG omega-3 fatty esters, ether, and alcohols, glycerol fattyesters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitanfatty esters, sugar fatty esters, PEG sugar esters and derivativesthereof.

In another embodiment, the coating layer overlying the surface of amedical device comprises a therapeutic agent and an additive, whereinthe additive is a surfactant.

In another embodiment, the additive is a chemical compound having one ormore hydroxyl, amino, carbonyl, carboxyl, acid, amide, ester groups. Inanother embodiment, the additive is a hydrophilic chemical compound withone or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or estergroups with a molecular weight of less than 5,000-10,000, preferablyless than 1000-5,000, more preferably less than 750-1,000, or mostpreferably less than 750. Molecular weight of the additive is preferredto be less than that of the drug to be delivered. Small molecules candiffuse quickly, and they easily release from the surface of thedelivery balloon, carrying drug with them. They quickly diffuse awayfrom drug when the drug binds tissue. The molecular weight of theadditives cannot be too low, however; additives with molecular weightless than 80 are not desirebale because they evaporate easily and arenot stable components of the coating. In another embodiment, theadditive is a combination of a surfactant and a chemical compound withone or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or estergroups. In another embodiment, the additive is a combination of an aminoalcohol and an organic acid; the combination is advantageous because itprevents instability that might otherwise arise due to reactivity ofacids or amines with drugs such as paclitaxel. In another embodiment,the additive is hydroxyl ketone, hydroxyl lactone, hydroxyl acid,hydroxyl ester, or hydroxyl amide. In another embodiment, the additiveis gluconolactone or ribonic acid lactone thereof. In yet anotherembodiment, the additive is chosen from meglumine/lactic acid,meglumine/gentisic acid, meglumine/acetic acid, lactobionic acid, Tween20/sorbitol, Tween 20/lactobionic acid, Tween 20/sugar or sugarderivatives and N-octanoyl N-methylglucamine. In another embodiment, theadditive is a vitamin or derivative thereof. In another embodiment, theadditive is an amino acid or derivative thereof. In another embodiment,the additive is a protein or derivative thereof. In another embodiment,the additive is an albumin. In another embodiment, the additive issoluble in an aqueous solvent and is soluble in an organic solvent. Inanother embodiment, the additive is an organic acid or an anhydridethereof. In yet another embodiment, the additive is chosen from sorbitanoleate and sorbitan fatty esters.

In another embodiment, the coating layer overlying the surface of amedical device comprises a therapeutic agent and an additive, whereinthe additive is water-soluble, and wherein the additive is a chemicalcompound that has a molecular weight of from 80 to 750.

In one embodiment, the layer overlying the exterior surface of themedical device does not include oil, a lipid, or a polymer. In anotherembodiment, the layer overlying the exterior surface of the medicaldevice does not include oil. In another embodiment, the layer overlyingthe exterior surface of the medical device does not include a polymer.In another embodiment, the layer overlying the exterior surface of themedical device does not include a purely hydrophobic additive. In oneembodiment, the additive is not a therapeutic agent. In anotherembodiment, the additive is not salicylic acid or salts thereof.

In another embodiment, the coating layer overlying the surface of amedical device comprises a therapeutic agent and an additive, whereinthe additive comprises a hydrophilic part and a drug affinity part,wherein the drug affinity part is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,and a part that has an affinity to the therapeutic agent by van derWaals interactions, and wherein the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, Tween 20, Tween 40, Tween 60, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerols, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, and derivatives and combinations thereof.

In one embodiment, the therapeutic agent is one of paclitaxel andanalogues thereof, rapamycin and analogues thereof, beta-lapachone andanalogues thereof, biological vitamin D and analogues thereof, and amixture of these therapeutic agents. In another embodiment, thetherapeutic agent is in combination with a second therapeutic agent,wherein the therapeutic agent is one of paclitaxel, rapamycin, andanalogues thereof, and wherein the second therapeutic agent is one ofbeta-lapachone, biological active vitamin D, and their analogues.

In one embodiment, the medical device comprising a layer overlying anexterior surface of the medical device further comprises an adherentlayer between the exterior surface of the medical device and the layer.In another embodiment, the device further comprises a top layeroverlying the surface of the layer to reduce loss of drug during transitthrough a body to the tissue. In another embodiment, the top layeroverlying the surface of the layer overlying the exterior surface of themedical device comprises an additive that is less hydrophilic than theadditive in the layer overlying the exterior surface of the medicaldevice, and wherein the additive of the top layer is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In another embodiment, the medical device further comprises adimethylsulfoxide solvent layer, wherein the dimethylsulfoxide solventlayer is overlying the surface of the layer.

In one embodiment of the medical device, the device is capable ofreleasing the therapeutic agent and the additive and deliveringtherapeutic agent to the tissue in about 0.1 to 2 minutes. In oneembodiment, the concentration of the therapeutic agent in the layer isfrom 1 to 20 μg/mm². In one embodiment, the concentration of thetherapeutic agent in the layer is from 2 to 10 μg/mm². In oneembodiment, the therapeutic agent is not water-soluble.

In one embodiment, the additive enhances release of the therapeuticagent off the balloon. In another embodiment, the additive enhancespenetration and absorption of the therapeutic agent in tissue. Inanother embodiment, the additive has a water and ethanol solubility ofat least 1 mg/ml and the therapeutic agent is not water-soluble.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andat least two additives, wherein each of the additives comprises ahydrophilic part and a drug affinity part, wherein the drug affinitypart is at least one of a hydrophobic part, a part that has an affinityto the therapeutic agent by hydrogen bonding, and a part that has anaffinity to the therapeutic agent by van der Waals interactions, andwherein each additive is soluble in polar organic solvent and is solublein water. In one aspect of this embodiment, the polar organic solvent ischosen from methanol, ethanol, isopropanol, acetone, dimethylformide,tetrahydrofuran, methylethyl ketone, dimethylsulfoxide, acetonitrile,ethyl acetate, and chloroform and mixtures of these polar organicsolvents with water. In another aspect of this embodiment, the devicefurther comprises a top layer overlying the surface of the layeroverlying the exterior surface of the medical device to reduce loss ofdrug during transit through a body to the target tissue.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and adrug affinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive reducescrystal size and number of particles of the therapeutic agent, andwherein the additive is water-soluble and the therapeutic agent is notwater-soluble.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and adrug affinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive has a fattychain of an acid, ester, ether, or alcohol, wherein the fatty chain candirectly insert into lipid membrane structures of the tissue, andwherein the therapeutic agent is not water-soluble.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and ahydrophobic part, wherein the additive can penetrate into and rearrangelipid membrane structures of the tissue, and wherein the therapeuticagent is not water-soluble and is not enclosed in micelles orencapsulated in polymer particles.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent andan additive, wherein the additive comprises a hydrophilic part and adrug affinity part, wherein the additive has a fatty chain of an acid,ester, ether, or alcohol, wherein the fatty chain directly inserts intolipid membrane structures of tissue, wherein the additive has one ormore functional groups which have affinity to the drug by hydrogenbonding and/or van der Waals interactions (the functional groups includehydroxyl, ester, amide, carboxylic acid, primary, second, and tertiaryamine, carbonyl, anhydrides, oxides, and amino alcohols), wherein thetherapeutic agent is not water-soluble and is not enclosed in micellesor encapsulated in polymer particles, and wherein the layer does notinclude a polymer, and the layer does not include an iodine covalentbonded contrast agent.

In yet another embodiment, the present invention relates to a stentcoating for delivering a therapeutic agent to a tissue, the stentcoating comprising a layer overlying a surface of the stent. In oneaspect of this embodiment, the layer overlying the surface of the stentcomprises a therapeutic agent, an additive, and a polymer matrix,wherein the therapeutic agent is dispersed, but not encapsulated, asparticles in the polymer matrix, wherein the additive comprises ahydrophilic part and a drug affinity part, wherein the drug affinity isat least one of a hydrophobic part, a part that has an affinity to thetherapeutic agent by hydrogen bonding, and a part that has an affinityto the therapeutic agent by van der Waals interactions. In one aspect ofthis embodiment, the additive improves the compatibility of thetherapeutic agent and the polymer matrix, the additive reduces theparticle sizes and improves uniformity of distribution of thetherapeutic agent in the polymer matrix, and the additive enhances rapidrelease of drug from the polymer matrix.

In yet another embodiment, the present invention relates to a medicaldevice coating for delivering a drug to a tissue that is prepared from amixture. In one aspect of this embodiment, the coating is prepared froma mixture comprising an organic phase containing drug particlesdispersed therein and an aqueous phase containing a water-solubleadditive. In one aspect of this embodiment, the water-soluble additiveis chosen from polyethylene glycol, polyvinyl alcohol,polyvinylpyrrolidinone, polypeptides, water-soluble surfactants,water-soluble vitamins, and proteins. In another aspect of thisembodiment, the preparation of the mixture includes homogenization underhigh shear conditions and optionally under pressure.

In another embodiment, the present invention relates to a ballooncatheter for delivering a therapeutic agent to a blood vessel, thecatheter comprising a coating layer overlying an exterior surface of aballoon. In one embodiment of the balloon catheter, the coating layercomprises a therapeutic agent and an additive, wherein the additivecomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,wherein the additive is water-soluble, and wherein the additive is atleast one of a surfactant and a chemical compound, and wherein thechemical compound has a molecular weight of from 80 to 750.

In another embodiment of the balloon catheter, the coating layercomprises a therapeutic agent and an additive, wherein the additivecomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,wherein the additive is at least one of a surfactant and a chemicalcompound, and wherein the chemical compound has more than four hydroxylgroups. In one aspect of this embodiment, the chemical compound havingmore than four hydroxyl groups has a melting point of 120° C. or less,and the chemical compound is an alcohol or an ester.

In one embodiment of the balloon catheter, the coating layer overlyingan exterior surface of the exterior surface of the medical deviceconsists essentially of the therapeutic agent and the additive. Inanother embodiment, the layer overlying the exterior surface of themedical device does not include an iodine covalent bonded contrastagent.

In one embodiment, the surfactant is chosen from ionic, nonionic,aliphatic, and aromatic surfactants, PEG fatty esters, PEG omega-3 fattyesters, ether, and alcohols, glycerol fatty esters, sorbitan fattyesters, PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugarfatty esters, PEG sugar esters and derivatives thereof. In oneembodiment, the chemical compound has one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, thechemical compound having one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester groups is chosen from amino alcohols,hydroxyl carboxylic acid, ester, and anhydrides, hydroxyl ketone,hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyloxide, ethyl glycols, amino acids, peptides, proteins, sorbitan,glycerol, polyalcohol, phosphates, sulfates, organic acids, esters,salts, vitamins, combinations of amino alcohol and organic acid, andtheir substituted molecules.

In one embodiment of the balloon catheter, the coating layer overlyingthe exterior surface of the balloon does not include a purelyhydrophobic additive. In another embodiment, the coating layer overlyingthe surface of the balloon does not contain an iodinated contrast agent.In another embodiment, the additive is not a therapeutic agent. Inanother embodiment, the additive is not salicylic acid or salts thereof.In another embodiment, the coating layer overlying the surface of theballoon does not include oil, a lipid, or a polymer. In yet anotherembodiment, the coating layer overlying the surface of the balloon doesnot include oil. In another aspect of this embodiment, the coating layerdoes not include a polymer.

In one embodiment of the balloon catheter, the additive in the coatinglayer comprising the therapeutic agent and the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In one embodiment, the therapeutic agent is one of paclitaxel andanalogues thereof, rapamycin and analogues thereof, beta-lapachone andanalogues thereof, biological vitamin D and analogues thereof, and amixture of these therapeutic agents. In another embodiment, thetherapeutic agent is in combination with a second therapeutic agent,wherein the therapeutic agent is one of paclitaxel, rapamycin, andanalogues thereof, and wherein the second therapeutic agent is one ofbeta-lapachone, biological active vitamin D, and their analogues. In oneembodiment, the therapeutic agent is not water soluble.

In one embodiment, the additive is soluble in an organic solvent and inwater. In another embodiment, the additive enhances penetration andabsorption of the therapeutic agent in tissue of the blood vessel. Inanother embodiment, the therapeutic agent is not water-soluble. Inanother embodiment, the additive has water and ethanol solubility of atleast 1 mg/ml, and the therapeutic agent is not water-soluble.

In one embodiment of the balloon catheter, the catheter furthercomprises an adherent layer between the exterior surface of the balloonand the coating layer. In another embodiment, the catheter furthercomprises a top layer overlying the coating layer, wherein the top layerreduces loss of the therapeutic agent during transit through a body tothe blood vessel. The top layer comprises an additive selected fromthose additives, according to embodiments of the invention describedherein. The top layer will be slowly dissolved during transit through abody to the body lumen to the target site for therapeutic intervention.This top layer will reduce drug loss during transit and increase thedrug available to the tissue when the medical device of embodiments ofthe present invention is pressed into contact with luminal tissue. Inone embodiment, the additive in the top layer is less hydrophilic thanthe additive in the coating layer. In another embodiment, the catheterfurther comprises a dimethylsulfoxide solvent layer, wherein thedimethylsulfoxide solvent layer is overlying the surface of the coatinglayer.

In one embodiment, the balloon catheter is capable of releasing thetherapeutic agent and the additive and delivering the therapeutic agentto the blood vessel in about 0.1 to 2 minutes.

In one embodiment of the balloon catheter, the concentration of thetherapeutic agent in the coating layer is from 1 to 20 μg/mm². Inanother embodiment, the concentration of the therapeutic agent in thecoating layer is from 2 to 10 μg/mm².

In yet a further embodiment, the present invention relates to a ballooncatheter for delivering a therapeutic agent to a blood vessel. In oneaspect of this embodiment, the catheter comprises an elongate memberhaving a lumen and a distal end, an expandable balloon attached to thedistal end of the elongate member and in fluid communication with thelumen, and a coating layer overlying an exterior surface of the balloon.In one aspect of this embodiment, the coating layer overlying thesurface of the balloon comprises a therapeutic agent and an additive,wherein the additive comprises a hydrophilic part and a drug affinitypart, wherein the drug affinity part is at least one of a hydrophobicpart, a part that has an affinity to the therapeutic agent by hydrogenbonding, and a part that has an affinity to the therapeutic agent by vander Waals interactions, wherein the additive is water-soluble, whereinthe additive is at least one of a surfactant and a chemical compound,and wherein the chemical compound has a molecular weight of from 80 to750, and wherein the catheter is capable of releasing the therapeuticagent and the additive and delivering the therapeutic agent to tissue ofthe blood vessel in less than about 2 minutes. In one aspect of thisembodiment, the layer does not contain an iodinated contrast agent.

In one embodiment, the balloon catheter further comprises adimethylsulfoxide solvent layer overlying the coating layer, wherein thedimethylsulfoxide layer enhances the ability of the therapeutic agent topenetrate into the blood vessel. In another embodiment, the ballooncatheter further comprises an adherent layer between the exteriorsurface of the balloon and the coating layer. In yet another embodiment,the balloon catheter further comprises a top layer overlying the coatinglayer, wherein the top layer maintains integrity of the coating layerduring transit through a blood vessel to the target site for therapeuticintervention.

In one embodiment, the concentration of the therapeutic agent in thecoating layer is from 2.5 to 6 μg/mm². In one embodiment, the surfactantis chosen from ionic, nonionic, aliphatic, and aromatic surfactants, PEGfatty esters, PEG omega-3 fatty esters, ether, and alcohols, glycerolfatty esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEGsorbitan fatty esters, sugar fatty esters, PEG sugar esters andderivatives thereof. In one embodiment, the chemical compound has one ormore hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups.In one embodiment, the chemical compound having one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups is chosen fromamino alcohols, hydroxylcarboxylic acid, ester, and anhydrides, hydroxylketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugarsulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins,sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids,esters, salts, vitamins, combinations of amino alcohol and organic acid,and their substituted molecules. In one embodiment, the chemicalcompound has more than four hydroxyl groups and has a melting point of120° C. or less, and the chemical compound is an alcohol or an ester.

In one embodiment of the balloon catheter, the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, Tween 20, Tween 40, Tween 60, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In yet a further embodiment, the present invention relates to apharmaceutical composition comprising a therapeutic agent and anadditive, wherein the additive comprises a hydrophilic part and a drugaffinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive iswater-soluble, wherein the additive is at least one of a surfactant anda chemical compound, and wherein the chemical compound has a molecularweight of from 80 to 750. In one aspect of this embodiment, thepharmaceutical composition does not include an iodine covalent bondedcontrast agent or a polymer, and wherein the therapeutic agent is notencapsulated in miscelles or particles.

In one embodiment, the chemical compound has one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups. In oneembodiment, the chemical compound having one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups is chosen from aminoalcohols, hydroxylcarboxylic acid, ester, and anhydrides, hydroxylketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugarsulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins,sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids,esters, salts, vitamins, combinations of amino alcohol and organic acid,and their substituted molecules. In one embodiment, the chemicalcompound has more than four hydroxyl groups and has a melting point of120° C. or less, and the chemical compound is an alcohol or an ester. Inone embodiment, the surfactant is chosen from ionic, nonionic,aliphatic, and aromatic surfactants, PEG fatty esters, PEG omega-3 fattyesters, ether, and alcohols, glycerol fatty esters, sorbitan fattyesters, PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugarfatty esters, PEG sugar esters and derivatives thereof.

In one embodiment of the pharmaceutical composition, the additive ischosen from p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEGstearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glycerylstearate, polyglyceryl laurate, Tween 20, Tween 40, Tween 60,plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In yet a further embodiment, the present invention relates to a methodfor treating a diseased body lumen or cavity after a surgical orinterventional procedure comprising delivering a pharmaceuticalcomposition at a surgical site by injection or spraying with a catheter,wherein the composition comprises a therapeutic agent and an additive,wherein the additive comprises a hydrophilic part and a drug affinitypart, wherein the drug affinity part is at least one of a hydrophobicpart, a part that has an affinity to the therapeutic agent by hydrogenbonding, and a part that has an affinity to the therapeutic agent by vander Waals interactions, wherein the additive is at least one of asurfactant and a chemical compound, and wherein the chemical compoundhas a molecular weight of from 80 to 750. In one embodiment, thechemical compound has one or more hydroxyl, amino, carbonyl, carboxyl,acid, amide or ester groups. In one embodiment, the additive iswater-soluble, and wherein the composition does not include an iodinecovalent bonded contrast agent.

In one embodiment, the surfactant is chosen from ionic, nonionic,aliphatic, and aromatic surfactants, PEG fatty esters, PEG omega-3 fattyesters, ether, and alcohols, glycerol fatty esters, sorbitan fattyesters, PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugarfatty esters, PEG sugar esters and derivatives thereof. In oneembodiment, the chemical compound having one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups is chosen from aminoalcohols, hydroxyl carboxylic acid, ester, and anhydrides, hydroxylketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugarsulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins,sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids,esters, salts, vitamins, combinations of amino alcohol and organic acid,and their substituted molecules.

In yet a further embodiment, the present invention relates to apharmaceutical composition for treating a cancer including cancers ofthe ovary, breast, lung, esophagus, head and neck region, bladder,prostate, brain, liver, colon and lymphomas, wherein the compositioncomprises a therapeutic agent and an additive, wherein the additivecomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,wherein the therapeutic agent is not enclosed in micelles orencapsulated in polymer particles, and wherein the composition does notinclude an iodine covalent bonded contrast agent. In one aspect of thisembodiment, the therapeutic agent is chosen from paclitaxel andanalogues thereof and rapamycin and analogues thereof.

In yet a further embodiment, the present invention relates to a solutionfor coating a medical device. In one aspect of this embodiment, thesolution comprises an organic solvent, a therapeutic agent, and anadditive, wherein the additive comprises a hydrophilic part and a drugaffinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive iswater-soluble, wherein the additive is at least one of a surfactant anda chemical compound, and wherein the chemical compound has a molecularweight of from 80 to 750. In another embodiment, the solution forcoating a medical device does not include an iodine covalent bondedcontrast agent, an oil, a lipid, or a polymer.

In one embodiment, the chemical compound has one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups. In oneembodiment, the chemical compound having one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups is chosen from aminoalcohols, hydroxyl carboxylic acid, ester, and anhydrides, hydroxylketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugarsulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins,sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids,esters, salts, vitamins, combinations of amino alcohol and organic acid,and their substituted molecules. In one embodiment, the surfactant ischosen from ionic, nonionic, aliphatic, and aromatic surfactants, PEGfatty esters, PEG omega-3 fatty esters, ether, and alcohols, glycerolfatty esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEGsorbitan fatty esters, sugar fatty esters, PEG sugar esters andderivatives thereof. In one embodiment, the therapeutic agent ispaclitaxel or rapamycin or analog or derivative thereof.

In another embodiment, the additive in the coating solution is chosenfrom wherein the additive is chosen from p-isononylphenoxypolyglycidol,PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, Tween 20,tween 60, Tween 80, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine; acetic anhydride, benzoic anhydride, ascorbic acid,2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid; cetotiamine; cyclothiamine,dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a first layer applied to an exterior surface of the medicaldevice, and a second layer overlying the first layer. In one aspect ofthis embodiment, the first layer comprises a therapeutic agent, and thesecond layer comprises an additive, wherein the additive comprises ahydrophilic part and a drug affinity part, wherein the drug affinitypart is at least one of a hydrophobic part, a part that has an affinityto the therapeutic agent by hydrogen bonding, and a part that has anaffinity to the therapeutic agent by van der Waals interactions. In oneaspect of this embodiment, the first layer further comprises anadditive, wherein the additive is water-soluble and the layer does notinclude an iodinated contrast agent. In another aspect of thisembodiment, the second layer further comprises a therapeutic agent. Inyet a further aspect of this embodiment, the first layer furthercomprises an additive and the second layer further comprises atherapeutic agent.

In a further embodiment, the present invention relates to a two layercoating comprising a first layer comprising a therapeutic agent, and atop layer comprising an additive. In one aspect of this embodiment, thetop layer may be overlying the first layer. In one aspect of thisembodiment, the additive in both the first layer and in the top layercomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,wherein the additive is water-soluble, wherein the additive is at leastone of a surfactant and a chemical compound, and wherein the chemicalcompound has a molecular weight of from 80 to 750. In one aspect of thisembodiment, the first layer does not include an iodine covalent bondedcontrast agent. In another aspect of this embodiment, the top layerfurther comprises a therapeutic agent.

In a further embodiment, the present invention relates to a method forpreparing a medical device. In one aspect of this embodiment, the methodcomprises (a) preparing a coating solution comprising an organicsolvent, a therapeutic agent, and an additive, wherein the additivecomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,wherein the additive is water-soluble, wherein the additive is at leastone of a surfactant and a chemical compound, and wherein the chemicalcompound has a molecular weight of from 80 to 750, (b) applying thecoating solution to a medical device, and (c) drying the coatingsolution, forming a coating layer. In one aspect of this embodiment, thecoating layer does not include an iodine covalent bonded contrast agent.In one aspect of this embodiment, the coating solution is applied bydipping a portion of the exterior surface of the medical device in thecoating solution. In another aspect of this embodiment, the coatingsolution is applied by spraying a portion of the exterior surface of themedical device with a coating solution. In another aspect of thisembodiment, steps (b) and (c) are repeated until a therapeuticallyeffective amount of the therapeutic agent in the coating layer isdeposited on the surface of the medical device. In another aspect ofthis embodiment, the total thickness of the coating layer is from about0.1 to 200 microns. In yet another aspect of this embodiment, the methodfurther comprises applying a dimethylsulfoxide solvent to the driedcoating layer obtained in step (c).

In a further embodiment, the present invention relates to a method forpreparing a drug coated balloon catheter. In one aspect of thisembodiment, the method comprises, (a) preparing a coating solutioncomprising an organic solvent, a therapeutic agent, and an additive,wherein the additive comprises a hydrophilic part and a drug affinitypart, wherein the drug affinity is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,and a part that has an affinity to the therapeutic agent by van derWaals interactions, wherein the additive is at least one of a surfactantand a chemical compound, and wherein the chemical compound has amolecular weight of from 80 to 750, (b) applying the coating solution toan inflated balloon catheter, and (c) deflating and folding the ballooncatheter and drying the coating solution to increase uniformity of drugcoating.

In a further embodiment, the present invention relates to a method fortreating a blood vessel. In one aspect of this embodiment, the methodcomprises inserting a medical device comprising a coating layer into theblood vessel, wherein the coating layer comprises a therapeutic agentand an additive, wherein the additive comprises a hydrophilic part and adrug affinity part, wherein the drug affinity is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive iswater-soluble, wherein the additive is at least one of a surfactant anda chemical compound, and wherein the chemical compound has a molecularweight of from 80 to 750, and releasing the therapeutic agent and theadditive and delivering the therapeutic agent into the tissue of theblood vessel in 2 minutes or less. In one aspect of this embodiment, thecoating layer does not include an iodine covalent bonded contrast agent.

In a further embodiment, the present invention relates to a method fortreating a total occlusion or narrowing of body passages. In one aspectof this embodiment, the method comprises removing plaques from the bodypassage, inserting a medical device comprising a coating layer into thebody passage, wherein the coating layer comprises a therapeutic agentand an additive, wherein the additive comprises a hydrophilic part and adrug affinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive is at leastone of a surfactant and a chemical compound, and wherein the chemicalcompound has a molecular weight of from 80 to 750, and releasing thetherapeutic agent and the additive and delivering the therapeutic agentinto the tissue of the body passage in 2 minutes or less.

In a further embodiment, the present invention relates to a method fortreating tissue of a body comprising bringing a medical devicecomprising a coating layer into contact with tissue of the body, whereinthe coating layer comprises a therapeutic agent and an additive, whereinthe additive comprises a hydrophilic part and a drug affinity part,wherein the drug affinity part is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,and a part that has an affinity to the therapeutic agent by van derWaals interactions, wherein the additive is water-soluble, wherein theadditive is at least one of a surfactant and a chemical compound, andwherein the chemical compound has a molecular weight of from 80 to 750,and releasing the therapeutic agent and the additive and delivering thetherapeutic agent into the tissue in 2 minutes or less. In oneembodiment, the coating layer does not include an iodine covalentcontrast agent. In one aspect of this embodiment, the tissue includestissue of one of coronary vasculature, peripheral vasculature, cerebralvasculature, esophagus, airways, sinus, trachea, colon, biliary tract,urinary tract, prostate, and brain passages.

In yet a further embodiment, the present invention relates to a processof producing a balloon catheter. In one aspect of this embodiment, theprocess comprises preparing a solution comprising an organic solvent, atherapeutic agent, and an additive, wherein the additive comprises ahydrophilic part and a drug affinity part, wherein the drug affinity isat least one of a hydrophobic part, a part that has an affinity to thetherapeutic agent by hydrogen bonding, and a part that has an affinityto the therapeutic agent by van der Waals interactions, wherein theadditive is water-soluble, wherein the additive is at least one of asurfactant and a chemical compound, and wherein the chemical compoundhas a molecular weight of from 80 to 750, applying the solution to theballoon catheter, and evaporating the solvent. In one embodiment, thesolution does not contain an iodinated contrast agent.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is one of PEG fatty ester, PEG fatty ether, and PEGfatty alcohols. In one aspect of this embodiment, the additive is chosenfrom wherein the additive is chosen from PEG-8 laurate, PEG-8 oleate,PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, PEG-20 oleate,PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurateand PEG-32 dioleate. In another aspect of this embodiment, the tissueincludes tissue of one of coronary vasculature, peripheral vasculature,cerebral vasculature, esophagus, airways, sinus, trachea, colon, biliarytract, urinary tract, prostate, and brain passages. In yet anotheraspect of this embodiment, the device includes one of a ballooncatheter, a perfusion balloon catheter, an infusion catheter, a cuttingballoon catheter, a scoring balloon catheter, a laser catheter, anatherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is one of glycerol and polyglycerol fatty estersand PEG glycerol fatty esters. In one aspect of this embodiment, theadditive is chosen from polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl linoleate,polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono,dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and polyglyceryl-6linoleate, polyglyceryl polyricinoleates, PEG-20 glyceryl laurate,PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryloleate, and PEG-30 glyceryl oleate. In another aspect of thisembodiment, the tissue includes tissue of one of coronary vasculature,peripheral vasculature, cerebral vasculature, esophagus, airways, sinus,trachea, colon, biliary tract, urinary tract, prostate, and brainpassages. In yet another aspect of this embodiment, the device includesone of a balloon catheter, a perfusion balloon catheter, an infusioncatheter, a cutting balloon catheter, a scoring balloon catheter, alaser catheter, an atherectomy device, a debulking catheter, a stent, afilter, a stent graft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is one of sorbitan fatty esters, and PEG sorbitanesters. In one aspect of this embodiment, the additive is chosen fromsorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate,sorbitan monostearate, PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonopalmitate, PEG-20 sorbitan monooleate, and PEG-20 sorbitanmonostearate. In another aspect of this embodiment, the tissue includestissue of one of coronary vasculature, peripheral vasculature, cerebralvasculature, esophagus, airways, sinus, trachea, colon, biliary tract,urinary tract, prostate, and brain passages. In yet another aspect ofthis embodiment, the device includes one of a balloon catheter, aperfusion balloon catheter, an infusion catheter, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is a chemical compound containing a phenol moiety.In one aspect of this embodiment, the additive is chosen fromp-isononylphenoxypolyglycidol, octoxynol, monoxynol, tyloxapol,octoxynol-9, and monoxynol-9. In another aspect of this embodiment, thetissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages. Inyet another aspect of this embodiment, the device includes one of aballoon catheter, a perfusion balloon catheter, an infusion catheter, acutting balloon catheter, a scoring balloon catheter, a laser catheter,an atherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive, theadditive is chosen from sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside, D-glucoascorbic acid and its salt,tromethamine, glucamine, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, and glucosamine. In another aspect ofthis embodiment, the tissue includes tissue of one of coronaryvasculature, peripheral vasculature, cerebral vasculature, esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,and brain passages. In yet another aspect of this embodiment, the deviceincludes one of a balloon catheter, a perfusion balloon catheter, aninfusion catheter, a cutting balloon catheter, a scoring ballooncatheter, a laser catheter, an atherectomy device, a debulking catheter,a stent, a filter, a stent graft, a covered stent, a patch, a wire, anda valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is an ionic surfactant. In one aspect of thisembodiment, the additive is chosen from benzalkonium chloride,benzethonium chloride, cetylpyridinium chloride, docecyl trimethylammonium bromide, sodium docecylsulfates, dialkyl methylbenzyl ammoniumchloride, edrophonium chloride, domiphen bromide, dialkylesters ofsodium sulfonsuccinic acid, sodium dioctyl sulfosuccinate, sodiumcholate, and sodium taurocholate. In another aspect of this embodiment,the tissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages. Inyet another aspect of this embodiment, the device includes one of aballoon catheter, a perfusion balloon catheter, infusion catheter, acutting balloon catheter, a scoring balloon catheter, a laser catheter,an atherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is a vitamin or vitamin derivative. In one aspectof this embodiment, the additive is chosen from acetiamine,benfotiamine, pantothenic acid, cetotiamine, cyclothiamine,dexpanthenol, niacinamide, nicotinic acid and its salts, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, vitamin U,ergosterol, 1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3,alpha-carotene, beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K—S(II). In another aspect of this embodiment, the tissueincludes tissue of one of coronary vasculature, peripheral vasculature,cerebral vasculature, esophagus, airways, sinus, trachea, colon, biliarytract, urinary tract, prostate, and brain passages. In yet anotheraspect of this embodiment, the device includes one of a ballooncatheter, a perfusion balloon catheter, infusion catheter, a cuttingballoon catheter, a scoring balloon catheter, a laser catheter, anatherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent and an additive,wherein the additive is an amino acid, an amino acid salt, or an aminoacid derivative. In one aspect of this embodiment, the additive ischosen from alanine, arginine, asparagine, aspartic acid, cysteine,glutamic acid, glutamine, glycine, histidine, proline, isoleucine,leucine, lysine, methionine, phenylalanine, serine, threonine,tryptophan, tyrosine, valine, and derivatives thereof. In another aspectof this embodiment, the tissue includes tissue of one of coronaryvasculature, peripheral vasculature, cerebral vasculature, esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,and brain passages. In yet another aspect of this embodiment, the deviceincludes one of a balloon catheter, a perfusion balloon catheter,infusion catheter, a cutting balloon catheter, a scoring ballooncatheter, a laser catheter, an atherectomy device, a debulking catheter,a stent, a filter, a stent graft, a covered stent, a patch, a wire, anda valve.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a layer overlying an exterior surface of the medical device,the layer comprising a therapeutic agent and an additive, wherein theadditive is a peptide, oligopeptide, or protein. In one aspect of thisembodiment, the additive is chosen from albumins, immunoglobulins,caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,fibronectins, vitronectins, firbinogens, and lipases. In another aspectof this embodiment, the tissue includes tissue of one of coronaryvasculature, peripheral vasculature, cerebral vasculature, esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,and brain passages. In yet another aspect of this embodiment, the deviceincludes one of a balloon catheter, a perfusion balloon catheter,infusion catheter, a cutting balloon catheter, a scoring ballooncatheter, a laser catheter, an atherectomy device, a debulking catheter,a stent, a filter, a stent graft, a covered stent, a patch, a wire, anda valve.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a layer overlying an exterior surface of the medical device,the layer comprising a therapeutic agent and an additive, wherein theadditive includes a combination or mixture of both a surfactant and achemical compound, wherein the chemical compound has one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In oneaspect of this embodiment, the surfactant is chosen from ionic,nonionic, aliphatic, and aromatic surfactants, PEG fatty esters, PEGomega-3 fatty esters, ether, and alcohols, glycerol fatty esters,sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitan fattyesters, sugar fatty esters, PEG sugar esters and derivatives thereof. Inanother aspect of this embodiment, the chemical compound having one ormore hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groupshas a molecular weight of from 80 to 750. In another aspect of thisembodiment, the chemical compound is chosen from amino alcohols,hydroxyl carboxylic acid, ester, and anhydrides, hydroxyl ketone,hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyloxide, ethyl glycols, amino acids, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic acids, esters, salts, vitamins,combinations of amino alcohol and organic acid, and their substitutedmolecules. In another aspect of this embodiment, the chemical compoundhaving one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide orester groups is chosen from acetic acid and anhydride, benzoic acid andanhydride, diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic acid and anhydride, glutaricacid and anhydride, ascorbic acid, citric acid, tartaric acid, lacticacid, oxalic acid aspartic acid, nicotinic acid, L-ascorbic acid and itssalt, D-glucoascorbic acid and its salt, tromethamine, triethanolamine,diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonicacid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine,glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid,lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate,sugar sulphates, sinapic acid, vanillic acid, vanillin, methyl paraben,propyl paraben, xylitol, 2-ethoxyethanol, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine described above, polyglycidol, glycerol, multiglycerols,galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethyleneglycol), penta(ethylene glycol), poly(ethylene glycol) oligomers,di(propylene glycol), tri(propylene glycol), tetra(propylene glycol, andpenta(propylene glycol), poly(propylene glycol) oligomers, a blockcopolymer of polyethylene glycol and polypropylene glycol, andderivatives and combinations thereof. In another aspect of thisembodiment, the tissue includes tissue of one of coronary vasculature,peripheral vasculature, cerebral vasculature, esophagus, airways, sinus,trachea, colon, biliary tract, urinary tract, prostate, and brainpassages. In yet another aspect of this embodiment, the device includesone of a balloon catheter, a perfusion balloon catheter, infusioncatheter, a cutting balloon catheter, a scoring balloon catheter, alaser catheter, an atherectomy device, a debulking catheter, a stent, afilter, a stent graft, a covered stent, a patch, a wire, and a valve.

In another embodiment, the present invention relates to a pharmaceuticalformulation for administration to a mammal comprising paclitaxel orrapamycin or derivatives thereof; and a combination of both a surfactantand a chemical compound, wherein the chemical compound has one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups. In oneembodiment, the surfactant is chosen from ionic, nonionic, aliphatic,and aromatic surfactants, PEG fatty esters, PEG omega-3 fatty esters,ether, and alcohols, glycerol fatty esters, sorbitan fatty esters, PEGglyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty esters,PEG sugar esters and derivatives thereof. In one embodiment, thechemical compound having one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester groups has a molecular weight of from 80to 750. In one embodiment, the chemical compound having one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester groups ischosen from amino alcohols, hydroxyl carboxylic acid, ester, andanhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugarphosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids,peptides, proteins, sugars, glucose, sucrose, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic acids, esters, salts,vitamins, combinations of amino alcohol and organic acid, and theirsubstituted molecules. In one embodiment, the chemical compound havingone or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or estergroups is chosen from L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben,acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid,catechin, catechin gallate, tiletamine, ketamine, propofol, lacticacids, acetic acid, ribonic acid lactone, meglumine/lactic acid,meglumine/gentisic acid, meglumine/acetic acid, sorbitol, xylitol,2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose, sucrose,lactose, maltose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, salts ofany organic acid and organic amine, polyglycidol, glycerol,multiglycerols, galactitol, di(ethylene glycol), tri(ethylene glycol),tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol)oligomers, di(propylene glycol), tri(propylene glycol), tetra(propyleneglycol, and penta(propylene glycol), poly(propylene glycol) oligomers, ablock copolymer of polyethylene glycol and polypropylene glycol, andderivatives and combinations thereof.

In another embodiment, the present invention relates to a pharmaceuticalformulation for administration to a mammal comprising paclitaxel orrapamycin or derivatives thereof, and a chemical compound with one ormore hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester groups,wherein the chemical compound with one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups has a molecular weightof from 80 to 750. In one embodiment, the chemical compound with one ormore hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester groupsis chosen from hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, sugar phosphate, sugar sulfate,catechin, catechin gallate, and combinations of amino alcohol andorganic acid. In one aspect of this embodiment, the amino alcohol ischosen from tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, glucosamine, lysine, and derivatives thereof; and the organicacid is chosen from glucoheptonic acid, glucomic acid, glutamic acid,benzoic acid, hydroxybenzoic acid, gentisic acid, lactobionic acid,vanillic acid, lactic acids, acetic acid, and derivatives thereof.

In yet another embodiment, the present invention relates to apharmaceutical formulation for administration to a mammal comprising:paclitaxel or rapamycin or derivatives thereof; and a combination ofamino alcohol and organic acid, wherein the amino alcohol is chosen fromtromethamine, triethanolamine, diethanolamine, meglumine, glucamine,glucosamine, lysine, and derivatives thereof; and the organic acid ischosen from glucoheptonic acid, glucomic acid, glutamic acid, benzoicacid, hydroxybenzoic acid, gentisic acid, lactobionic acid, vanillicacid, lactic acids, acetic acid, and derivatives thereof.

In yet another embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a layer overlying an exterior surface of the medical device,the layer comprising a therapeutic agent and an additive, wherein theadditive is chosen from hydroxyl ketone, hydroxyl lactone,gluconolactone, glucoheptonolactone, glucooctanoic lactone, gulonic acidlactone, mannoic lactone, ribonic acid lactone and lactobionic acid.

In yet another embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a layer overlying an exterior surface of the medical device,the layer comprising a therapeutic agent and an additive, wherein thetherapeutic agent is paclitaxel and analogues thereof or rapamycin andanalogues thereof, and the additive is chosen from sorbitol, diethyleneglycol, triethylene glycol, tetraethylene glycol, polyethylene glycololigomers, polypropylene glycol oligomers, block copolymer oligomers ofpolyethylene glycol and polypropylene glycol, xylitol, 2-ethoxyethanol,sugars, galactose, glucose, mannose, xylose, sucrose, lactose, maltose,Tween 20, Tween 40, Tween 60, and their derivatives, wherein the ratioby weight of drug to additive is from 0.5 to 3, wherein the therapeuticagent and the additive are simultaneously released.

Many embodiments of the present invention are particularly useful fortreating vascular disease and for reducing stenosis and late luminalloss, or are useful in the manufacture of devices for that purpose.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an exemplary embodiment of a ballooncatheter according to the present invention.

FIGS. 2A-2C are cross-sectional views of different embodiments of thedistal portion of the balloon catheter of FIG. 1, taken along line A-A,showing exemplary coating layers.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Embodiments of the present invention relate to medical devices,including particularly balloon catheters and stents, having a rapiddrug-releasing coating and methods for preparing such coated devices.The therapeutic agent according to embodiments of the present inventiondoes not require a delayed or long term release and instead preferablythe therapeutic agent and the additive are released in a very short timeperiod to provide a therapeutic effect upon contact with tissue. Anobject of embodiments of the present invention is to facilitate rapidand efficient uptake of drug by target tissue during transitory devicedeployment at a target site.

As shown in FIG. 1, in one embodiment, the medical device is a ballooncatheter. The balloon catheter may be any suitable catheter for thedesired use, including conventional balloon catheters known to one ofordinary skill in the art. For example, balloon catheter 10 may includean expandable, inflatable balloon 12 at a distal end of the catheter 10,a handle assembly 16 at a proximal end of the catheter 10, and anelongate flexible member 14 extending between the proximal and distalends. Handle assembly 16 may connect to and/or receive one or moresuitable medical devices, such as a source of inflation media (e.g.,air, saline, or contrast media). Flexible member 14 may be a tube madeof suitable biocompatible material and having one or more lumenstherein. At least one of the lumens is configured to receive inflationmedia and pass such media to balloon 12 for its expansion. The ballooncatheter may be a rapid exchange or over-the-wire catheter and made ofany suitable biocompatible material.

In one embodiment, the present invention provides a medical device fordelivering a therapeutic agent to a tissue. The device includes a layerapplied to an exterior surface of the medical device, such as a ballooncatheter or stent, for example. The layer includes a therapeutic agentand an additive. For example, as shown in the embodiment depicted inFIG. 2A, the balloon 12 is coated with a layer 20 that includes atherapeutic agent and an additive. In some embodiments, the layerconsists essentially of a therapeutic agent and an additive, i.e., thelayer includes only the therapeutic agent and the additive, without anyother materially significant components. In some embodiments, the devicemay optionally include an adherent layer. For example, as shown in theembodiment depicted in FIG. 2B, the balloon 12 is coated with anadherent layer 22. A layer 24 that includes a therapeutic agent and anadditive is overlying the adherent layer. The adherent layer, which is aseparate layer underlying the drug coating layer, improves the adherenceof the drug coating layer to the exterior surface of the medical deviceand protects coating integrity. For example, if drug and additive differin their adherence to the medical device, the adherent layer may preventdifferential loss of components and maintain drug-to-additive ratio inthe coating during transit to a target site for therapeuticintervention. Furthermore, the adherent layer may function to facilitaterapid release of coating layer components off the device surface uponcontact with tissues at the target site. In other embodiments, thedevice may include a top layer. The top layer may reduce loss of thedrug layer before it is brought into contact with target tissues, forexample during transit of the balloon 12 to the site of therapeuticintervention or during the first moments of inflation of balloon 12before coating layer 20 is pressed into direct contact with targettissue.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or more preferably from about 2 to 6 μg/mm². Theratio by weight of therapeutic agent to the additive is from about 0.5to 100, for example, from about 0.1 to 5, from 0.5 to 3, and further forexample, from about 0.8 to 1.2. If the ratio (by weight) of thetherapeutic agent to the additive is too low, then drug may releaseprematurely, and if the ratio is too high, then drug may not elutequickly enough or be absorbed by tissue when deployed at the targetsite.

In another embodiment, the layer comprises a therapeutic agent and anadditive, wherein the therapeutic agent is paclitaxel and analoguesthereof or rapamycin and analogues thereof, and the additive is chosenfrom sorbitol, diethylene glycol, triethylene glycol, tetraethyleneglycol, xylitol, 2-ethoxyethanol, sugars, galactose, glucose, mannose,xylose, sucrose, lactose, maltose, Tween 20, Tween 40, Tween 60, andtheir derivatives, wherein the ratio by weight of the therapeutic agentto the additive is from 0.5 to 3. If the ratio of drug to additive isbelow 0.5, then drug may release prematurely, and if ratio is above 3,then drug may not elute quickly enough or be absorbed by tissue whendeployed at the target site. In other embodiments, the layer may includea therapeutic agent and more than one additive. For example, oneadditive may serve to improve balloon adhesion of another additive oradditives that are superior at promoting drug release or tissue uptakeof drug.

In other embodiments, the layer may include at least one therapeuticagent, at least one additive, and at least one polymer carrier forcoating of a medical device such as a stent or a balloon. Thetherapeutic agent is not encapsulated in polymer particles. The additivein the layer improves compatibility of the drug and polymer carrier. Itreduces the size or eliminates drug crystal particles in the polymermatrix of the coating. The uniform drug distribution in the coatingimproves clinical outcomes by more uniformly delivering drug to targettissues.

In another embodiment, the device comprises two layers applied to anexterior surface of the medical device, and particularly a ballooncatheter, for example. The first layer comprises a therapeutic agent.The first layer may optionally comprise an additive or additives. Thesecond layer comprises an additive or additives. The second layer mayoptionally include at least a therapeutic agent. When the first andsecond layers both contain a therapeutic agent, the content of thetherapeutic agent in the second layer is lower than the content of thetherapeutic agent in the first layer. In one embodiment, the secondlayer is overlying the first layer. In this arrangement, the secondlayer can prevent drug loss during deployment of the medical device intobody passageways, for example, as a balloon catheter traverses thetortuous anatomy to a tissue site in the vasculature.

In another embodiment, the device comprises two layers applied to anexterior surface of the medical device, and particularly a ballooncatheter, for example. The first layer comprises a therapeutic agent.The first layer may optionally comprise an additive or additives. Thesecond layer comprises an additive or additives. The second layer mayoptionally include at least a therapeutic agent. When the first andsecond layers both contain a therapeutic agent, the content of thetherapeutic agent in the first layer is lower than the content of thetherapeutic agent in the second layer. In one embodiment, the secondlayer is overlying the first layer. This arrangement is useful, forexample, in the case of a therapeutic agent that adheres too tightly tothe balloon surface to rapidly elute off the balloon when inflated atthe target site. In this arrangement, the first layer functions tofacilitate rapid release of the bulk of drug, which is in the secondlayer, off the surface of the device while it is inflated at the targetsite of therapeutic intervention.

In other embodiments, two or more therapeutic agents are used incombination in the drug-additive layer.

In a further embodiment, the device having a two layer coating mayoptionally include an adherent layer. The adherent layer does notcontain a therapeutic agent. For example, as shown in the embodimentdepicted in FIG. 2C, the balloon 12 is coated with an adherent layer 22.A first layer 26 that comprises a therapeutic agent and optionally anadditive or additives is overlying the adherent layer 22. A second layer28 that comprises an additive and optionally a therapeutic agent isoverlying the first layer 26. The adherent layer improves the adherenceof the first layer to the exterior surface of the medical device andprotects the integrity of the first layer. For example, if drug andadditive or additives in the first layer differ in their strength ofadherence to the medical device, the adherent layer may preventdifferential loss of components and maintain drug-to-additive andadditive-to-additive ratio in the first and second layers during transitto a target site for therapeutic intervention. Furthermore, the adherentlayer may function to facilitate rapid elution of coating layer off thedevice surface upon contact with tissues at the target site. In oneembodiment, the first layer, the second layer, and the adherent layereach contain an additive.

Optionally, post-treatment with dimethylsulfoxide (DMSO) or othersolvent may be advantageous since DMSO may further enhance penetrationand absorption of drug into tissue. DMSO displaces water from the lipidhead groups and protein domains of the membrane lipid bilayer of targetcells to indirectly loosen the lipid structure, accelerating drugabsorption and penetration.

In a further embodiment, the present invention relates to apharmaceutical composition for treating a diseased body lumen orcavities after surgical or interventional procedures (PTCA, PTA, stentplacement, excision of diseased tissue such as cancer, and relieving ortreating stenosis), wherein the pharmaceutical composition comprises atherapeutic agent and an additive, wherein the additive comprises ahydrophilic part and a drug affinity part, wherein the drug affinitypart is a hydrophobic part and/or has an affinity to the therapeuticagent by hydrogen bonding and/or van der Waals interactions, and whereinthe therapeutic agent is not enclosed in micelles or encapsulated inpolymer particles.

In another embodiment, a method of preventing complications orrecurrence of disease (such as cancer or restenosis) after a surgical orinterventional procedure such as PTCA, PTA, stent deployment, stenosisor plaque removal by debulking, atherectomy, or laser procedures, thepharmaceutical composition is locally delivered at or near the site ofintervention by means of a coated medical device (such as a drug-coatedballoon), or by spray, by injection, or by deposition. For example, thepharmaceutical composition may be delivered by spray, injection, balloonor other method of deposition, into cavities created by surgical removalof cancer tissue in order to reduce the risk of recurrence. As anotherexample, a method for delivering the pharmaceutical compositioncomprises inserting a medical device (such as guide catheter or a druginfusion catheter) into the blood to inject the pharmaceuticalcomposition after a vascular intervention such as PTCA, PTA, or stentplacement to prevent restenosis, wherein the pharmaceutical compositioncomprises a therapeutic agent and an additive, wherein the additivecomprises a hydrophilic part and a drug affinity part, wherein the drugaffinity part is a hydrophobic part and/or has an affinity to thetherapeutic agent by hydrogen bonding and/or Van der Waals interactions,and wherein the therapeutic agent is not enclosed in micelles orencapsulated in polymer particles.

Many embodiments of the present invention are particularly useful fortreating vascular disease and for reducing stenosis and late luminalloss, or are useful in the manufacture of devices for that purpose or inmethods of treating that disease.

Additive

The additive of embodiments of the present invention has two parts. Onepart is hydrophilic and the other part is a drug affinity part. The drugaffinity part is a hydrophobic part and/or has an affinity to thetherapeutic agent by hydrogen bonding and/or van der Waals interactions.The drug affinity part of the additive may bind the lipophilic drug,such as rapamycin or paclitaxel. The hydrophilic portion acceleratesdiffusion and increases permeation of the drug into tissue. It mayfacilitate rapid movement of drug off the medical device duringdeployment at the target site by preventing hydrophobic drug moleculesfrom clumping to each other and to the device, increasing drugsolubility in interstitial spaces, and/or accelerating drug passagethrough polar head groups to the lipid bilayer of cell membranes oftarget tissues. The additives of embodiments of the present inventionhave two parts that function together to facilitate rapid release ofdrug off the device surface and uptake by target tissue duringdeployment (by accelerating drug contact with tissues for which drug hashigh affinity) while preventing the premature release of drug from thedevice surface prior to device deployment at the target site.

In embodiments of the present invention, the therapeutic agent israpidly released after the medical device is brought into contact withtissue and is readily absorbed. For example, certain embodiments ofdevices of the present invention include drug coated balloon cathetersthat deliver a lipophilic anti-proliferative pharmaceutical (such aspaclitaxel or rapamycin) to vascular tissue through brief, directpressure contact at high drug concentration during balloon angioplasty.The lipophilic drug is preferentially retained in target tissue at thedelivery site, where it inhibits hyperplasia and restenosis yet allowsendothelialization. In these embodiments, coating formulations of thepresent invention not only facilitate rapid release of drug from theballoon surface and transfer of drug into target tissues duringdeployment, but also prevent drug from diffusing away from the deviceduring transit through tortuous arterial anatomy prior to reaching thetarget site and from exploding off the device during the initial phaseof balloon inflation, before the drug coating is pressed into directcontact with the surface of the vessel wall.

The additive according to certain embodiments has a drug affinity partand a hydrophilic part. The drug affinity part is a hydrophobic partand/or has an affinity to the therapeutic agent by hydrogen bondingand/or van der Waals interactions. The drug affinity part may includealiphatic and aromatic organic hydrocarbon compounds, such as benzene,toluene, and alkanes, among others. These parts are not water soluble.They may bind both hydrophobic drug, with which they share structuralsimilarities, and lipids of cell membranes. They have no covalentlybonded iodine. The drug affinity part may include functional groups thatcan form hydrogen bonds with drug and with itself. The hydrophilic partmay include hydroxyl groups, amine groups, amide groups, carbonylgroups, carboxylic acid and anhydrides, ethyl oxide, ethyl glycol,polyethylene glycol, ascorbic acid, amino acid, amino alcohol, glucose,sucrose, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organicsalts and their substituted molecules, among others. One or morehydroxyl, carboxyl, acid, amide or amine groups, for example, may beadvantageous since they easily displace water molecules that arehydrogen-bound to polar head groups and surface proteins of cellmembranes and may function to remove this barrier between hydrophobicdrug and cell membrane lipid. These parts can dissolve in water andpolar solvents. These additives are not oils, lipids, or polymers. Thetherapeutic agent is not enclosed in micelles or liposomes orencapsulated in polymer particles. The additive of embodiments of thepresent invention has components to both bind drug and facilitate itsrapid movement off the medical device during deployment and into targettissues.

The additives in embodiments of the present invention are surfactantsand chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties. The surfactants include ionic,nonionic, aliphatic, and aromatic surfactants. The chemical compoundswith one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide orester moieties are chosen from amino alcohols, hydroxyl carboxylic acidand anhydrides, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic acids, esters, salts, vitamins, and theirsubstituted molecules.

As is well known in the art, the terms “hydrophilic” and “hydrophobic”are relative terms. To function as an additive in exemplary embodimentsof the present invention, the compound includes polar or chargedhydrophilic moieties as well as non-polar hydrophobic (lipophilic)moieties.

An empirical parameter commonly used in medicinal chemistry tocharacterize the relative hydrophilicity and hydrophobicity ofpharmaceutical compounds is the partition coefficient, P, the ratio ofconcentrations of unionized compound in the two phases of a mixture oftwo immiscible solvents, usually octanol and water, such thatP=([solute]octanol/[solute]water). Compounds with higher log Ps are morehydrophobic, while compounds with lower log Ps are more hydrophilic.Lipinski's rule suggests that pharmaceutical compounds having log P<5are typically more membrane permeable. For purposes of certainembodiments of the present invention, it is preferable that the additivehas log P less than log P of the drug to be formulated (as an example,log P of paclitaxel is 7.4). A greater log P difference between the drugand the additive can facilitate phase separation of drug. For example,if log P of the additive is much lower than log P of the drug, theadditive may accelerate the release of drug in an aqueous environmentfrom the surface of a device to which drug might otherwise tightlyadhere, thereby accelerating drug delivery to tissue during briefdeployment at the site of intervention. In certain embodiments of thepresent invention, log P of the additive is negative. In otherembodiments, log P of the additive is less than log P of the drug. Whilea compound's octanol-water partition coefficient P or log P is useful asa measurement of relative hydrophilicity and hydrophobicity, it ismerely a rough guide that may be useful in defining suitable additivesfor use in embodiments of the present invention.

Suitable additives that can be used in embodiments of the presentinvention include, without limitation, organic and inorganicpharmaceutical excipients, natural products and derivatives thereof(such as sugars, vitamins, amino acids, peptides, proteins, and fattyacids), low molecular weight oligomers, surfactants (anionic, cationic,non-ionic, and ionic), and mixtures thereof. The following detailed listof additives useful in the present invention is provided for exemplarypurposes only and is not intended to be comprehensive. Many otheradditives may be useful for purposes of the present invention.

Surfactants

The surfactant can be any surfactant suitable for use in pharmaceuticalcompositions. Such surfactants can be anionic, cationic, zwitterionic ornon-ionic. Mixtures of surfactants are also within the scope of theinvention, as are combinations of surfactant and other additives.Surfactants often have one or more long aliphatic chains such as fattyacids that may insert directly into lipid bilayers of cell membranes toform part of the lipid structure, while other components of thesurfactants loosen the lipid structure and enhance drug penetration andabsorption. The contrast agent iopromide does not have these properties.

An empirical parameter commonly used to characterize the relativehydrophilicity and hydrophobicity of surfactants is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more hydrophobic, and have greater solubility in oils, whilesurfactants with higher HLB values are more hydrophilic, and havegreater solubility in aqueous solutions. Using HLB values as a roughguide, hydrophilic surfactants are generally considered to be thosecompounds having an HLB value greater than about 10, as well as anionic,cationic, or zwitterionic compounds for which the HLB scale is notgenerally applicable. Similarly, hydrophobic surfactants are compoundshaving an HLB value less than about 10. In certain embodiments of thepresent invention, a higher HLB value is preferred, since increasedhydrophilicity may facilitate release of hydrophobic drug from thesurface of the device. In one embodiment, the HLB of the surfactantadditive is higher than 10. In another embodiment, the additive HLB ishigher than 14. Alternatively, surfactants having lower HLB may bepreferred when used to prevent drug loss prior to device deployment atthe target site, for example in a top coat over a drug layer that has avery hydrophilic additive.

It should be understood that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions, for example. For many importantsurfactants, including several polyethoxylated surfactants, it has beenreported that HLB values can differ by as much as about 8 HLB units,depending upon the empirical method chosen to determine the HLB value(Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Keeping theseinherent difficulties in mind, and using HLB values as a guide,surfactants may be identified that have suitable hydrophilicity orhydrophobicity for use in embodiments of the present invention, asdescribed herein.

PEG-Fatty Acids and PEG-Fatty Acid Mono and Diesters

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Among the PEG-fatty acid monoesters, esters of lauric acid,oleic acid, and stearic acid are most useful in embodiments of thepresent invention. Preferred hydrophilic surfactants include PEG-8laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate,PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20laurate and PEG-20 oleate. The HLB values are in the range of 4-20.

Polyethylene glycol fatty acid diesters are also suitable for use assurfactants in the compositions of embodiments of the present invention.Most preferred hydrophilic surfactants include PEG-20 dilaurate, PEG-20dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. TheHLB values are in the range of 5-15.

In general, mixtures of surfactants are also useful in embodiments ofthe present invention, including mixtures of two or more commercialsurfactants as well as mixtures of surfactants with another additive oradditives. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and diesters.

Polyethylene Glycol Glycerol Fatty Acid Esters

Preferred hydrophilic surfactants are PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, andPEG-30 glyceryl oleate.

Alcohol-Oil Transesterification Products

A large number of surfactants of different degrees of hydrophobicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholwith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, or almond oil. Preferred alcohols include glycerol,propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, andpentaerythritol. Among these alcohol-oil transesterified surfactants,preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35),PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate(TAGAT® TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil(Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil(Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capricglycerides (Softigen 767). Preferred hydrophobic surfactants in thisclass include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castoroil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil(Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil(Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS),PEG-6 triolein (Labrafil® b M 2735 CS), PEG-8 corn oil (Labrafil® WL2609 BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almondglycerides (Crovol A40).

Polyglyceryl Fatty Acids

Polyglycerol esters of fatty acids are also suitable surfactants for usein embodiments of the present invention. Among the polyglyceryl fattyacid esters, preferred hydrophobic surfactants include polyglyceryloleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO),polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate. Preferred hydrophilic surfactants include polyglyceryl-10laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn1-O), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860),polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate.Polyglyceryl polyricinoleates (Polymuls) are also preferred surfactants.

Propylene Glycol Fatty Acid Esters

Esters of propylene glycol and fatty acids are suitable surfactants foruse in embodiments of the present invention. In this surfactant class,preferred hydrophobic surfactants include propylene glycol monolaurate(Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propyleneglycol monooleate (Myverol P-O6), propylene glycol dicaprylate/dicaprate(Captex® 200), and propylene glycol dioctanoate (Captex® 800).

Sterol and Sterol Derivatives

Sterols and derivatives of sterols are suitable surfactants for use inembodiments of the present invention. Preferred derivatives include thepolyethylene glycol derivatives. A preferred surfactant in this class isPEG-24 cholesterol ether (Solulan C-24).

Polyethylene Glycol Sorbitan Fatty Acid Esters

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in embodiments of the present invention.Among the PEG-sorbitan fatty acid esters, preferred surfactants includePEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate(Tween-40), PEG-20 sorbitan monostearate (Tween-60). Laurate esters arepreferred because they have a short lipid chain compared with oleateesters, increasing drug absorption.

Polyethylene Glycol Alkyl Ethers

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in embodiments of the present invention. Preferredethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij30).

Sugar and Its Derivatives

Sugar derivatives are suitable surfactants for use in embodiments of thepresent invention. Preferred surfactants in this class include sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, andoctyl-β-D-thioglucopyranoside.

Polyethylene Glycol Alkyl Phenols

Several PEG-alkyl phenol surfactants are available, such as PEG-10-100nonyl phenol and PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, and are suitable for use in embodiments of the presentinvention.

Polyoxyethylene-Polyoxypropylene (POE-POP) Block Copolymers

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and hydrophobic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in embodimentsof the present invention. These surfactants are available under varioustrade names, including Synperonic PE series (101); Pluronic® series(BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, andPlurodac. The generic term for these polymers is “poloxamer” (CAS9003-11-6). These polymers have the formula:

HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H where “a” and “b” denote the numberof polyoxyethylene and polyoxypropylene units, respectively.

Preferred hydrophilic surfactants of this class include Poloxamers 108,188, 217, 238, 288, 338, and 407. Preferred hydrophobic surfactants inthis class include Poloxamers 124, 182, 183, 212, 331, and 335.

Sorbitan Fatty Acid Esters

Sorbitan esters of fatty acids are suitable surfactants for use inembodiments of the present invention. Among these esters, preferredhydrophobic surfactants include sorbitan monolaurate (Arlacel 20),sorbitan monopalmitate (Span-40), and sorbitan monooleate (Span-80),sorbitan monostearate.

The sorbitan monopalmitate, an amphiphilic derivative of Vitamin C(which has Vitamin C activity), can serve two important functions insolubilization systems. First, it possesses effective polar groups thatcan modulate the microenvironment. These polar groups are the samegroups that make vitamin C itself (ascorbic acid) one of the mostwater-soluble organic solid compounds available: ascorbic acid issoluble to about 30 wt/wt % in water (very close to the solubility ofsodium chloride, for example). And second, when the pH increases so asto convert a fraction of the ascorbyl palmitate to a more soluble salt,such as sodium ascorbyl palmitate.

Ionic Surfactants

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in embodimentsof the present invention. Preferred ionic surfactants include quaternaryammonium salts, fatty acid salts and bile salts. Specifically, preferredionic surfactants include benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, edrophoniumchloride, domiphen bromide, dialkylesters of sodium sulfonsuccinic acid,sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate.These quaternary ammonium salts are preferred additives. They can bedissolved in both organic solvents (such as ethanol, acetone, andtoluene) and water. This is especially useful for medical devicecoatings because it simplifies the preparation and coating process andhas good adhesive properties. Water insoluble drugs are commonlydissolved in organic solvents.

Some of the surfactants described herein are very stable under heating.They survive an ethylene oxide sterilization process. They do not reactwith drugs such as paclitaxel or rapamycin under the sterilizationprocess. The hydroxyl, ester, amide groups are preferred because theyare unlikely to react with drug, while amine and acid groups often doreact with paclitaxel or rapamycin during sterilization. Furthermore,surfactant additives improve the integrity and quality of the coatinglayer, so that particles do not fall off during handling. When thesurfactants described herein are formulated with paclitaxel,experimentally it protects drug from premature release during the devicedelivery process while facilitating rapid release and elution ofpaclitaxel during a very brief deployment time of 0.2 to 2 minutes atthe target site. Drug absorption by tissues at the target site isunexpectedly high experimentally.

Chemical Compounds with One or More Hydroxyl, Amino, Carbonyl, Carboxyl,Acid, Amide or Ester Moieties

The chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties include amino alcohols, hydroxylcarboxylic acid, ester, and anhydrides, hydroxyl ketone, hydroxyllactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide,ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic acids, esters, salts,vitamins, combinations of amino alcohols and organic acids, and theirsubstituted molecules. Hydrophilic chemical compounds with one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moietieshaving a molecular weight less than 5,000-10,000 are preferred incertain embodiments. In other embodiments, molecular weight of theadditive with one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide, or ester moieties is preferably less than 1000-5,000, or morepreferably less than 750-1,000, or most preferably less than 750. Inthese embodiments, the molecular weight of the additive is preferred tobe less than that of the drug to be delivered. Further, the molecularweight of the additive is preferred to be higher than 80 since moleculeswith molecular weight less than 80 very easily evaporate and do not stayin the coating of a medical device. Small molecules can diffuse quickly.They can release themselves easily from the delivery balloon,accelerating release of drug, and they can diffuse away from drug whenthe drug binds tissue of the body lumen.

In certain embodiments, more than four hydroxyl groups are preferred,for example in the case of a high molecular weight additive. Largemolecules diffuse slowly. If the molecular weight of the additive or thechemical compound is high, for example if the molecular weight is above800, above 1000, above 1200, above 1500, or above 2000; large moleculesmay elute off of the surface of the medical device too slowly to releasedrug under 2 minutes. If these large molecules contain more than fourhydroxyl groups they have increased hydrophilic properties, which isnecessary for relatively large molecules to release drug quickly. Theincreased hydrophilicity helps elute the coating off the balloon,accelerates release of drug, and improves or facilitates drug movementthrough water barrier and polar head groups of lipid bilayers topenetrate tissues. The hydroxyl group is preferred as the hydrophilicmoiety because it is unlikely to react with water insoluble drug, suchas paclitaxel or rapamycin. In some embodiments, the chemical compoundhaving more than four hydroxyl groups has a melting point of 120° C. orless. In some embodiments, the chemical compound having more than fourhydroxyl groups has three adjacent hydroxyl groups that in stereoconfiguration are all on one side of the molecule. For example, sorbitoland xylitol have three adjacent hydroxyl groups that instereoconfiguration are all on one side of the molecule, whilegalactitol does not. The difference impacts the physical properties ofthe isomers such as the melting temperature. The stereoconfiguration ofthe three adjacent hydroxyl groups may enhance drug binding. This willlead to improved compatibility of the water insoluble drug andhydrophilic additive, and improved tissue uptake and absorption of drug.

Some of the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties described herein are very stableunder heating. They survive an ethylene oxide sterilization process anddo not react with the water insoluble drug paclitaxel or rapamycinduring sterilization. L-ascorbic acid and its salt and diethanolamine,on the other hand, do not necessarily survive such a sterilizationprocess, and they react with paclitaxel. A different sterilizationmethod is therefore preferred for L-ascorbic acid and diethanolamine.Hydroxyl, ester, and amide groups are preferred because they areunlikely to react with therapeutic agents such as paclitaxel orrapamycin. Sometimes, amine and acid groups do react with paclitaxel,for example, experimentally, benzoic acid, gentisic acid,diethanolamine, and ascorbic acid were not stable under ethylene oxidesterilization, heating, and aging process and reacted with paclitaxel.When the chemical compounds described herein are formulated withpaclitaxel, a top coat layer may be advantageous in order to preventpremature drug loss during the device delivery process before deploymentat the target site, since hydrophilic small molecules sometimes releasedrug too easily. The chemical compounds herein rapidly elute drug offthe balloon during deployment at the target site. Surprisingly, eventhough some drug is lost during transit of the device to the target sitewhen the coating contains these additives, experimentally drugabsorption by tissue is unexpectedly high after only 0.2-2 minutes ofdeployment, for example, with the additive hydroxyl lactones such asribonic acid lactone and gluconolactone.

Fat-Soluble Vitamins and Salts Thereof

Vitamins A, D, E and K in many of their various forms and provitaminforms are considered as fat-soluble vitamins and in addition to these anumber of other vitamins and vitamin sources or close relatives are alsofat-soluble and have polar groups, and relatively high octanol-waterpartition coefficients. Clearly, the general class of such compounds hasa history of safe use and high benefit to risk ratio, making them usefulas additives in embodiments of the present invention.

The following examples of fat-soluble vitamin derivatives and/or sourcesare also useful as additives: Alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K—S(II). Folic acid is also of this type, and although it iswater-soluble at physiological pH, it can be formulated in the free acidform. Other derivatives of fat-soluble vitamins useful in embodiments ofthe present invention may easily be obtained via well known chemicalreactions with hydrophilic molecules.

Water-Soluble Vitamins and Their Amphiphilic Derivatives

Vitamins B, C, U, pantothenic acid, folic acid, and some of themenadione-related vitamins/provitamins in many of their various formsare considered water-soluble vitamins. These may also be conjugated orcomplexed with hydrophobic moieties or multivalent ions into amphiphilicforms having relatively high octanol-water partition coefficients andpolar groups. Again, such compounds can be of low toxicity and highbenefit to risk ratio, making them useful as additives in embodiments ofthe present invention. Salts of these can also be useful as additives inthe present invention. Examples of water-soluble vitamins andderivatives include, without limitation, acetiamine, benfotiamine,pantothenic acid, cetotiamine, cyclothiamine, dexpanthenol, niacinamide,nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,riboflavin, riboflavin phosphate, thiamine, folic acid, menadioldiphosphate, menadione sodium bisulfite, menadoxime, vitamin B12,vitamin K5, vitamin K6, vitamin K6, and vitamin U. Also, as mentionedabove, folic acid is, over a wide pH range including physiological pH,water-soluble, as a salt.

Compounds in which an amino or other basic group is present can easilybe modified by simple acid-base reaction with a hydrophobicgroup-containing acid such as a fatty acid (especially lauric, oleic,myristic, palmitic, stearic, or 2-ethylhexanoic acid), low-solubilityamino acid, benzoic acid, salicylic acid, or an acidic fat-solublevitamin (such as riboflavin). Other compounds might be obtained byreacting such an acid with another group on the vitamin such as ahydroxyl group to form a linkage such as an ester linkage, etc.Derivatives of a water-soluble vitamin containing an acidic group can begenerated in reactions with a hydrophobic group-containing reactant suchas stearylamine or riboflavine, for example, to create a compound thatis useful in embodiments of the present invention. The linkage of apalmitate chain to vitamin C yields ascorbyl palmitate.

Amino Acids and their Salts

Alanine, arginine, asparagines, aspartic acid, cysteine, cystine,glutamic acid, glutamine, glycine, histidine, proline, isoleucine,leucine, lysine, methionine, phenylalanine, serine, threonine,tryptophan, tyrosine, valine, and derivatives thereof are other usefuladditives in embodiments of the invention.

Certain amino acids, in their zwitterionic form and/or in a salt formwith a monovalent or multivalent ion, have polar groups, relatively highoctanol-water partition coefficients, and are useful in embodiments ofthe present invention. In the context of the present disclosure we take“low-solubility amino acid” to mean an amino acid which has a solubilityin unbuffered water of less than about 4% (40 mg/ml). These includeCystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,asparagine, aspartic acid, glutamic acid, and methionine.

Amino acid dimers, sugar-conjugates, and other derivatives are alsouseful. Through simple reactions well known in the art hydrophilicmolecules may be joined to hydrophobic amino acids, or hydrophobicmolecules to hydrophilic amino acids, to make additional additivesuseful in embodiments of the present invention.

Catecholamines, such as dopamine, levodopa, carbidopa, and DOPA, arealso useful as additives.

Oligopeptides, Peptides and Proteins

Oligopeptides and peptides are useful as additives, since hydrophobicand hydrophilic amino acids may be easily coupled and various sequencesof amino acids may be tested to maximally facilitate permeation oftissue by drug.

Proteins are also useful as additives in embodiments of the presentinvention. Serum albumin, for example, is a particularly preferredadditive since it is water-soluble and contains significant hydrophobicparts to bind drug: paclitaxel is 89% to 98% protein-bound after humanintravenous infusion, and rapamycin is 92% protein bound, primarily(97%) to albumin. Furthermore, paclitaxel solubility in PBS increasesover 20-fold with the addition of BSA. Albumin is naturally present athigh concentrations in serum and is thus very safe for humanintravascular use.

Other useful proteins include, without limitation, other albumins,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases, andthe like.

Organic Acids and their Esters and Anhydrides

Examples are acetic acid and anhydride, benzoic acid and anhydride,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acidaspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and2-pyrrolidone.

These esters and anhydrides are soluble in organic solvents such asethanol, acetone, methylethylketone, ethylacetate. The water insolubledrugs can be dissolved in organic solvent with these esters andanhydrides, then coated easily on to the medical device, then hydrolyzedunder high pH conditions. The hydrolyzed anhydrides or esters are acidsor alcohols, which are water soluble and can effectively carry the drugsoff the device into the vessel walls.

Other Chemical Compounds with One or More Hydroxyl, Amine, Carbonyl,Carboxyl, or Ester Moieties

The additives according to embodiments include amino alcohols, alcohols,amines, acids, amides and hydroxyl acids in both cyclo and linearaliphatic and aromatic groups. Examples are L-ascorbic acid and itssalt, D-glucoascorbic acid and its salt, tromethamine, triethanolamine,diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonicacid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine,glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid,lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate,sugar sulphates, sinapic acid, vanillic acid, vanillin, methyl paraben,propyl paraben, xylitol, 2-ethoxyethanol, sugars, galactose, glucose,ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose,fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and amine described above, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

Combinations of additives are also useful for purposes of the presentinvention.

One embodiment comprises the combination or mixture of two additives,for example, a first additive comprising a surfactant and a secondadditive comprising a chemical compound with one or more hydroxyl,amine, carbonyl, carboxyl, or ester moieties.

The combination or mixture of the surfactant and the small water-solublemolecule (the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties) has advantages. Formulationscomprising mixtures of the two additives with water-insoluble drug arein certain cases superior to mixtures including either additive alone.The hydrophobic drugs bind extremely water-soluble small molecules morepoorly than they do surfactants. They are often phase separated from thesmall water-soluble molecules, which can lead to suboptimal coatinguniformity and integrity. The water-insoluble drug has Log P higher thanboth that of the surfactant and that of small water-soluble molecules.However, Log P of the surfactant is typically higher than Log P of thechemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl,or ester moieties. The surfactant has a relatively high Log P (usuallyabove 0) and the water soluble molecules have low Log P (usually below0). Some surfactants, when used as additives in embodiments of thepresent invention, adhere so strongly to the water-insoluble drug andthe surface of the medical device that drug is not able to rapidlyrelease from the surface of the medical device at the target site. Onthe other hand, some of the water-soluble small molecules (with one ormore hydroxyl, amine, carbonyl, carboxyl, or ester moieties) adhere sopoorly to the medical device that they release drug before it reachesthe target site, for example, into serum during the transit of a coatedballoon catheter to the site targeted for intervention. Surprisingly, byadjusting the ratio of the concentrations of the small hydrophilicmolecule and the surfactant in the formulation, the inventor has foundthat the coating stability during transit and rapid drug release wheninflated and pressed against tissues of the lumen wall at the targetsite of therapeutic intervention in certain cases is superior to aformulation comprising either additive alone. Furthermore, themiscibility and compatibility of the water-insoluble drug and the highlywater-soluble molecules is improved by the presence of the surfactant.The surfactant also improves coating uniformity and integrity by itsgood adhesion to the drug and the small molecules. The long chainhydrophobic part of the surfactant binds drug tightly while thehydrophilic part of the surfactant binds the water-soluble smallmolecules.

The surfactants in the mixture or the combination include all of thesurfactants described herein for use in embodiments of the invention.The surfactant in the mixture may be chosen from PEG fatty esters, PEGomega-3 fatty esters and alcohols, glycerol fatty esters, sorbitan fattyesters, PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugarfatty esters, PEG sugar esters, Tween 20, Tween 40, Tween 60,p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, Tween 20, Tween 40, Tween 60, Tween 80,octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrosemonolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-13-D-thioglucopyranoside and theirderivatives.

The chemical compound with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties in the mixture or the combination includeall of the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties described herein for use inembodiments of the invention. The chemical compound with one or morehydroxyl, amine, carbonyl, carboxyl, or ester moieties in the mixturehas at least one hydroxyl group in one of the embodiments in theinventions. In certain embodiments, more than four hydroxyl groups arepreferred, for example in the case of a high molecular weight additive.In some embodiments, the chemical compound having more than fourhydroxyl groups has a melting point of 120° C. or less. Large moleculesdiffuse slowly. If the molecular weight of the additive or the chemicalcompound is high, for example if the molecular weight is above 800,above 1000, above 1200, above 1500, or above 2000; large molecules mayelute off of the surface of the medical device too slowly to releasedrug under 2 minutes. If these large molecules contain more than fourhydroxyl groups they have increased hydrophilic properties, which isnecessary for relatively large molecules to release drug quickly. Theincreased hydrophilicity helps elute the coating off the balloon,accelerates release of drug, and improves or facilitates drug movementthrough water barrier and polar head groups of lipid bilayers topenetrate tissues. The hydroxyl group is preferred as the hydrophilicmoiety because it is unlikely to react with water insoluble drug, suchas paclitaxel or rapamycin.

The chemical compound with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties in the mixture is chosen from L-ascorbicacid and its salt, D-glucoascorbic acid and its salt, tromethamine,triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols,glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone,gluconolactone, glucoheptonolactone, glucooctanoic lactone, gulonic acidlactone, mannoic lactone, ribonic acid lactone, lactobionic acid,glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoicacid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid,lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphates,glucopyranose phosphate, sugar sulphates, sinapic acid, vanillic acid,vanillin, methyl paraben, propyl paraben, xylitol, 2-ethoxyethanol,sugars, galactose, glucose, ribose, mannose, xylose, sucrose, lactose,maltose, arabinose, lyxose, fructose, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine described above, polyglycidol, glycerol, multiglycerols,galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethyleneglycol), penta(ethylene glycol), poly(ethylene glycol) oligomers,di(propylene glycol), tri(propylene glycol), tetra(propylene glycol, andpenta(propylene glycol), poly(propylene glycol) oligomers, a blockcopolymer of polyethylene glycol and polypropylene glycol, andderivatives and combinations thereof.

Mixtures or combinations of a surfactant and a water-soluble smallmolecule confer the advantages of both additives. The water insolubledrug often has a poor compatibility with highly water-soluble chemicalcompounds, and the surfactant improves compatibility. The surfactantalso improves the coating quality, uniformity, and integrity, andparticles do not fall off the balloon during handling. The surfactantreduces drug loss during transit to a target site. The water-solublechemical compound improves the release of drug off the balloon andabsorption of the drug in the tissue. Experimentally, the combinationwas surprisingly effective at preventing drug release during transit andachieving high drug levels in tissue after very brief 0.2-2 minutedeployment. Furthermore, in animal studies it effectively reducedarterial stenosis and late lumen loss.

Some of the mixtures or combinations of surfactants and water-solublesmall molecules are very stable under heating. They survived an ethyleneoxide sterilization process and do not react with the water insolubledrug paclitaxel or rapamycin during sterilization. The hydroxyl, ester,amide groups are preferred because they are unlikely to react withtherapeutic agents such as paclitaxel or rapamycin. Sometimes amine andacid groups do react with paclitaxel and are not stable under ethyleneoxide sterilization, heating, and aging. When the mixtures orcombinations described herein are formulated with paclitaxel, a top coatlayer may be advantageous in order to protect the drug layer and frompremature drug loss during the device.

Preferred additives include p-isononylphenoxypolyglycidol, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids); cetotiamine; cyclothiamine, dexpanthenol,niacinamide, nicotinic acid and its salt, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.(chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, or ester moieties). Some of these additives are bothwater-soluble and organic solvent-soluble. They have good adhesiveproperties and adhere to the surface of polyamide medical devices, suchas balloon catheters. They may therefore be used in the adherent layer,top layer, and/or in the drug layer of embodiments of the presentinvention. The aromatic and aliphatic groups increase the solubility ofwater insoluble drugs in the coating solution, and the polar groups ofalcohols and acids accelerate drug permeation of tissue.

Other preferred additives according to embodiments of the inventioninclude the combination or mixture or amide reaction products of anamino alcohol and an organic acid. Examples are lysine/glutamic acid,lysine acetate, lactobionic acid/meglumine, lactobionicacid/tromethanemine, lactobionic acid/diethanolamine, lacticacid/meglumine, lactic acid/tromethanemine, lactic acid/diethanolamine,gentisic acid/meglumine, gentisic acid/tromethanemine, gensiticacid/diethanolamine, vanillic acid/meglumine, vanillicacid/tromethanemine, vanillic acid/diethanolamine, benzoicacid/meglumine, benzoic acid/tromethanemine, benzoicacid/diethanolamine, acetic acid/meglumine, acetic acid/tromethanemine,and acetic acid/diethanolamine.

Other preferred additives according to embodiments of the inventioninclude hydroxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxylester, and hydroxyl amide. Examples are gluconolactone,D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, erythronic acid lactone, ribonic acid lactone,glucuronic acid, gluconic acid, gentisic acid, lactobionic acid, lacticacid, acetaminophen, vanillic acid, sinapic acid, hydroxybenzoic acid,methyl paraben, propyl paraben, and derivatives thereof.

Other preferred additives that may be useful in embodiments of thepresent invention include riboflavin, riboflavin-phosphate sodium,Vitamin D3, folic acid (vitamin B9), vitamin 12,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine.

From a structural point of view, these additives share structuralsimilarities and are compatible with water insoluble drugs (such aspaclitaxel and rapamycin). They often contain double bonds such as C═C,C═N, C═O in aromatic or aliphatic structures. These additives alsocontain amine, alcohol, ester, amide, anhydride, carboxylic acid, and/orhydroxyl groups. They may form hydrogen bonds and/or van der Waalsinteractions with drug. They are also useful in the top layer in thecoating. Compounds containing one or more hydroxyl, carboxyl, or aminegroups, for example, are especially useful as additives since theyfacilitate drug release from the device surface and easily displacewater next to the polar head groups and surface proteins of cellmembranes and may thereby remove this barrier to hydrophobic drugpermeability. They accelerate movement of a hydrophobic drug off theballoon to the lipid layer of cell membranes and tissues for which ithas very high affinity. They may also carry or accelerate the movementof drug off the balloon into more aqueous environments such as theinterstitial space, for example, of vascular tissues that have beeninjured by balloon angioplasty or stent expansion. Additives such aspolyglyceryl fatty esters, ascorbic ester of fatty acids, sugar esters,alcohols and ethers of fatty acids have fatty chains that can integrateinto the lipid structure of target tissue membranes, carrying drug tolipid structures. Some of the amino acids, vitamins and organic acidshave aromatic C═N groups as well as amino, hydroxyl, and carboxyliccomponents to their structure. They have structural parts that can bindor complex with hydrophobic drug, such as paclitaxel or rapamycin, andthey also have structural parts that facilitate tissue penetration byremoving barriers between hydrophobic drug and lipid structure of cellmembranes.

For example, isononylphenylpolyglycidol (Olin-10 G and Surfactant-10G),PEG glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate all have morethan four hydroxyl groups in their hydrophilic part. These hydroxylgroups have very good affinity for the vessel wall and can displacehydrogen-bound water molecules. At the same time, they have long chainsof fatty acid, alcohol, ether and ester that can both complex withhydrophobic drug and integrate into the lipid structure of the cellmembranes to form the part of the lipid structure. This deformation orloosening of the lipid membrane of target cells may further acceleratepermeation of hydrophobic drug into tissue.

For another example, L-ascorbic acid, thiamine, maleic acids,niacinamide, and 2-pyrrolidone-5-carboxylic acid all have a very highwater and ethanol solubility and a low molecular weight and small size.They also have structural components including aromatic C═N, amino,hydroxyl, and carboxylic groups. These structures have very goodcompatibility with paclitaxel and rapamycin and can increase thesolubility of these water-insoluble drugs in water and enhance theirabsorption into tissues. However, they often have poor adhesion to thesurface of medical devices. They are therefore preferably used incombination with other additives in the drug layer and top layer wherethey are useful to enhance drug absorption. Vitamin D2 and D3 areespecially useful because they themselves have anti-restenotic effectsand reduce thrombosis, especially when used in combination withpaclitaxel.

In embodiments of the present invention, the additive is soluble inaqueous solvents and is soluble in organic solvents. Extremelyhydrophobic compounds that lack sufficient hydrophilic parts and areinsoluble in aqueous solvent, such as the dye Sudan Red, are not usefulas additives in these embodiments. Sudan red is also genotoxic.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or more preferably from about 2 to 6 μg/mm². Inone embodiment, the concentration of the at least one additive appliedto the surface of the medical device is from about 1 to 20 μg/mm². Theratio of additives to drug by weight in the coating layer in embodimentsof the present invention is about 20 to 0.05, preferably about 10 to0.5, or more preferably about 5 to 0.8.

The relative amount of the therapeutic agent and the additive in thecoating layer may vary depending on applicable circumstances. Theoptimal amount of the additive can depend upon, for example, theparticular therapeutic agent and additive selected, the critical micelleconcentration of the surface modifier if it forms micelles, thehydrophilic-lipophilic-balance (HLB) of a surfactant or an additive'soctonol-water partition coefficient (P), the melting point of theadditive, the water solubility of the additive and/or therapeutic agent,the surface tension of water solutions of the surface modifier, etc.

The additives are present in exemplary coating compositions ofembodiments of the present invention in amounts such that upon dilutionwith an aqueous solution, the carrier forms a clear, aqueous dispersionor emulsion or solution, containing the hydrophobic therapeutic agent inaqueous and organic solutions. When the relative amount of surfactant istoo great, the resulting dispersion is visibly “cloudy”.

The optical clarity of the aqueous dispersion can be measured usingstandard quantitative techniques for turbidity assessment. Oneconvenient procedure to measure turbidity is to measure the amount oflight of a given wavelength transmitted by the solution, using, forexample, an UV-visible spectrophotometer. Using this measure, opticalclarity corresponds to high transmittance, since cloudier solutions willscatter more of the incident radiation, resulting in lower transmittancemeasurements.

Another method of determining optical clarity and carrier diffusivitythrough the aqueous boundary layer is to quantitatively measure the sizeof the particles of which the dispersion is composed. These measurementscan be performed on commercially available particle size analyzers.

Other considerations will further inform the choice of specificproportions of different additives. These considerations include thedegree of bioacceptability of the additives and the desired dosage ofhydrophobic therapeutic agent to be provided.

Therapeutic Agent

The drugs or biologically active materials, which can be used inembodiments of the present invention, can be any therapeutic agent orsubstance. The drugs can be of various physical states, e.g., moleculardistribution, crystal forms or cluster forms. Examples of drugs that areespecially useful in embodiments of the present invention are lipophilicsubstantially water insoluble drugs, such as paclitaxel, rapamycin,daunorubicin, doxorubicin, lapachone, vitamin D2 and D3 and analoguesand derivatives thereof. These drugs are especially suitable for use ina coating on a balloon catheter used to treat tissue of the vasculature.

Other drugs that may be useful in embodiments of the present inventioninclude, without limitation, glucocorticoids (e.g., dexamethasone,betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisenseagents, anti-cancer agents, anti-proliferative agents, oligonucleotides,and, more generally, anti-platelet agents, anti-coagulant agents,anti-mitotic agents, antioxidants, anti-metabolite agents,anti-chemotactic, and anti-inflammatory agents.

Also useful in embodiments of the present invention are polynucleotides,antisense, RNAi, or siRNA, for example, that inhibit inflammation and/orsmooth muscle cell or fibroblast proliferation.

Anti-platelet agents can include drugs such as aspirin and dipyridamole.Aspirin is classified as an analgesic, antipyretic, anti-inflammatoryand anti-platelet drug. Dipyridamole is a drug similar to aspirin inthat it has anti-platelet characteristics. Dipyridamole is alsoclassified as a coronary vasodilator. Anti-coagulant agents for use inembodiments of the present invention can include drugs such as heparin,protamine, hirudin and tick anticoagulant protein. Anti-oxidant agentscan include probucol. Anti-proliferative agents can include drugs suchas amlodipine and doxazosin. Anti-mitotic agents and anti-metaboliteagents that can be used in embodiments of the present invention includedrugs such as methotrexate, azathioprine, vincristine, vinblastine,5-fluorouracil, adriamycin, and mutamycin. Antibiotic agents for use inembodiments of the present invention include penicillin, cefoxitin,oxacillin, tobramycin, and gentamicin. Suitable antioxidants for use inembodiments of the present invention include probucol. Additionally,genes or nucleic acids, or portions thereof can be used as thetherapeutic agent in embodiments of the present invention. Furthermore,collagen-synthesis inhibitors, such as tranilast, can be used as atherapeutic agent in embodiments of the present invention.

Photosensitizing agents for photodynamic or radiation therapy, includingvarious porphyrin compounds such as porfimer, for example, are alsouseful as drugs in embodiments of the present invention.

Drugs for use in embodiments of the present invention also includeeverolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin,ascomycin, bafilomycin, erythromycin, midecamycin, josamycin,concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin,simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin,pravastatin, pitavastatin, vinblastine, vincristine, vindesine,vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine,cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan,ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine,busulfan, procarbazine, treosulfan, temozolomide, thiotepa,daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone,idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate,fludarabine, fludarabine-5′-dihydrogenphosphate, cladribine,mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine,capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine,irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin,aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole,exemestane, letrozole, formestane, aminoglutethimide, adriamycin,azithromycin, spiramycin, cepharantin, smc proliferation inhibitor-2w,epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil,c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin,lapachol, beta.-lapachone, podophyllotoxin, betulin, podophyllic acid2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b,lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab,daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines,cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin,camptothecin, fluoroblastin, monoclonal antibodies, which inhibit themuscle cell proliferation, bFGF antagonists, probucol, prostaglandins,1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one,scopoletin, colchicine, NO donors such as pentaerythritol tetranitrateand syndnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine,beta.-estradiol, a-estradiol, estriol, estrone, ethinylestradiol,fosfestrol, medroxyprogesterone, estradiol cypionates, estradiolbenzoates, tranilast, kamebakaurin and other terpenoids, which areapplied in the therapy of cancer, verapamil, tyrosine kinase inhibitors(tyrphostines), cyclosporine A, 6-a-hydroxy-paclitaxel, baccatin,taxotere and other macrocyclic oligomers of carbon suboxide (MCS) andderivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac,dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamicacid, piroxicam, meloxicam, chloroquine phosphate, penicillamine,hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol,celecoxib, .beta.-sitosterin, ademetionine, myrtecaine, polidocanol,nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851(Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, S 100protein, bacitracin, vitronectin receptor antagonists, azelastine,guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and-2, free nucleic acids, nucleic acids incorporated into virustransmitters, DNA and RNA fragments, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, antisense oligonucleotides, VEGFinhibitors, IGF-1, active agents from the group of antibiotics such ascefadroxil, cefazolin, cefaclor, cefotaxim, tobramycin, gentamycin,penicillins such as dicloxacillin, oxacillin, sulfonamides,metronidazol, antithrombotics such as argatroban, aspirin, abciximab,synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulphatedand N-reacetylated heparin, tissue plasminogen activator, GpIIb/IIIaplatelet membrane receptor, factor Xa inhibitor antibody, heparin,hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase,warfarin, urokinase, vasodilators such as dipyramidole, trapidil,nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin,ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril,losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferona, .beta and y, histamine antagonists, serotonin blockers, apoptosisinhibitors, apoptosis regulators such as p65 NF-kB or Bcl-xL antisenseoligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, Boswellicacids and derivatives thereof, leflunomide, anakinra, etanercept,sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone,mutamycin, procainamide, retinoic acid, quinidine, disopyramide,flecamide, propafenone, sotalol, amidorone, natural and syntheticallyobtained steroids such as bryophyllin A, inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen,ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviralagents such as acyclovir, ganciclovir and zidovudine, antimycotics suchas clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole,nystatin, terbinafine, antiprozoal agents such as chloroquine,mefloquine, quinine, moreover natural terpenoids such as hippocaesculin,barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7,tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides Nand P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, Cand D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal,maytenfoliol, effusantin A, excisanin A and B, longikaurin B,sculponeatin C, kamebaunin, leukamenin A and B,13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, regenilol,triptolide, moreover cymarin, apocymarin, aristolochic acid, anopterin,hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburinchloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavoneA, curcumin, dihydronitidine, nitidine chloride,12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid,helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol,glycoside 1a, podophyllotoxin, justicidin A and B, larreatin,malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A,marchantin A, maytansine, lycoridicin, margetine, pancratistatin,liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-All,bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid,deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid,methylsorbifolin, sphatheliachromen, stizophyllin, mansonine,strebloside, akagerine, dihydrousambarensine, hydroxyusambarine,strychnopentamine, strychnophylline, usambarine, usambarensine,berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol,methoxylariciresinol, syringaresinol, umbelliferon, afromoson,acetylvismione B, desacetylvismione A, and vismione A and B.

A combination of drugs can also be used in embodiments of the presentinvention. Some of the combinations have additive effects because theyhave a different mechanism, such as paclitaxel and rapamycin, paclitaxeland active vitamin D, paclitaxel and lapachone, rapamycin and activevitamin D, rapamycin and lapachone. Because of the additive effects, thedose of the drug can be reduced as well. These combinations may reducecomplications from using a high dose of the drug.

Adherent Layer

The adherent layer, which is an optional layer underlying the drugcoating layer, improves the adherence of the drug coating layer to theexterior surface of the medical device and protects coating integrity.If drug and additive differ in their adherence to the medical device,the adherent layer may prevent differential loss (during transit) orelution (at the target site) of drug layer components in order tomaintain consistent drug-to-additive or drug-to-drug ratio in the druglayer and therapeutic delivery at the target site of intervention.Furthermore, the adherent layer may function to facilitate release ofcoating layer components which otherwise might adhere too strongly tothe device for elution during brief contact with tissues at the targetsite. For example, in the case where a particular drug binds the medicaldevice tightly, more hydrophilic components are incorporated into theadherent layer in order to decrease affinity of the drug to the devicesurface.

As described above, the adherent layer comprises a polymer or anadditive or mixtures of both. The polymers that are useful for formingthe adherent layer are ones that are biocompatible and avoid irritationof body tissue. Some examples of polymers that are useful for formingthe adherent layer are polymers that are biostable, such aspolyurethanes, silicones, and polyesters. Other polymers that are usefulfor forming the adherent layer include polymers that can be dissolvedand polymerized on the medical device.

Some examples of polymers that are useful in the adherent layer ofembodiments of the present invention include polyolefins,polyisobutylene, ethylene-a-olefin copolymers, acrylic polymers andcopolymers, polyvinyl chloride, polyvinyl methyl ether, polyvinylidenefluoride and polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polystyrene, polyvinyl acetate, ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, ABS resins, Nylon 12 andits block copolymers, polycaprolactone, polyoxymethylenes, polyethers,epoxy resins, polyurethanes, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, carboxymethyl cellulose, chitins,polylactic acid, polyglycolic acid, polylactic acid-polyethylene oxidecopolymers, polyethylene glycol, polypropylene glycol, polyvinylalcohol, and mixtures and block copolymers thereof.

Since the medical device undergoes mechanical manipulation, i.e.,expansion and contraction, examples of polymers that are useful in theadherent layer include elastomeric polymers, such as silicones (e.g.,polysiloxanes and substituted polysiloxanes), polyurethanes,thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefinelastomers, and EPDM rubbers. Due to the elastic nature of thesepolymers, when these polymers are used, the coating better adheres tothe surface of the medical device when the device is subjected to forcesor stress.

The adherent layer may also comprise one or more of the additivespreviously described, or other components, in order to maintain theintegrity and adherence of the coating layer to the device and tofacilitate both adherence of drug and additive components during transitand rapid elution during deployment at the site of therapeuticintervention.

Top Layer

In order to further protect the integrity of the drug layer, an optionaltop layer may be applied to prevent loss of drug during transit throughtortuous anatomy to the target site or during the initial expansion ofthe device before the coating makes direct contact with target tissue.The top layer may release slowly in the body lumen while protecting thedrug layer. The top layer will erode more slowly if it is comprised ofmore hydrophobic, high molecular weight additives. Surfactants areexamples of more hydrophobic structures with long fatty chains, such asTween 20 and polyglyceryl oleate. High molecular weight additivesinclude polyethylene oxide, polyethylene glycol, and polyvinylpyrrolidone. Hydrophobic drug itself can act as a top layer component.For example, paclitaxel or rapamycin are hydrophobic. They can be usedin the top layer. On the other hand, the top layer cannot erode tooslowly or it might actually slow the release of drug during deploymentat the target site. Other additives useful in the top coat includeadditives that strongly interact with drug or with the coating layer,such as p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

Solvents

Solvents for preparing of the coating layer may include, as examples,any combination of one or more of the following: (a) water, (b) alkanessuch as hexane, octane, cyclohexane, and heptane, (c) aromatic solventssuch as benzene, toluene, and xylene, (d) alcohols such as ethanol,propanol, and isopropanol, diethylamide, ethylene glycol monoethylether, Trascutol, and benzyl alcohol (e) ethers such as dioxane,dimethyl ether and tetrahydrofuran, (f) esters/acetates such as ethylacetate and isobutyl acetate, (g) ketones such as acetone, acetonitrile,diethyl ketone, and methyl ethyl ketone, and (h) mixture of water andorganic solvents such as water/ethanol, water/acetone, water/methanol,water/tetrahydrofuran. A preferred solvent in the top coating layer isacetone.

Organic solvents, such as short-chained alcohol, dioxane,tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide,etc., are particularly useful and preferred solvents in embodiments ofthe present invention because these organic solvents generally disruptcollodial aggregates and co-solubilize all the components in the coatingsolution.

The therapeutic agent and additive or additives may be dispersed in,solubilized, or otherwise mixed in the solvent. The weight percent ofdrug and additives in the solvent may be in the range of 0.1-80% byweight, preferably 2-20% by weight.

Another embodiment of the invention relates to a method for preparing amedical device, particularly, for example, a balloon catheter or astent. First, a coating solution or suspension comprising at least onesolvent, at least one therapeutic agent, and at least one additive isprepared. In at least one embodiment, the coating solution or suspensionincludes only these three components. The content of the therapeuticagent in the coating solution can be from 0.5-50% by weight based on thetotal weight of the solution. The content of the additive in the coatingsolution can be from 1-45% by weight, 1 to 40% by weight, or from 1-15%by weight based on the total weight of the solution. The amount ofsolvent used depends on the coating process and viscosity. It willaffect the uniformity of the drug-additive coating but will beevaporated.

In other embodiments, two or more solvents, two or more therapeuticagents, and/or two or more additives may be used in the coatingsolution.

In other embodiments, a therapeutic agent, an additive and a polymericmaterial may be used in the coating solution, for example in a stentcoating. In the coating, the therapeutic agent is not encapsulated inpolymer particles.

Various techniques may be used for applying a coating solution to amedical device such as casting, spinning, spraying, dipping (immersing),ink jet printing, electrostatic techniques, and combinations of theseprocesses. Choosing an application technique principally depends on theviscosity and surface tension of the solution. In embodiments of thepresent invention, dipping and spraying are preferred because it makesit easier to control the uniformity of the thickness of the coatinglayer as well as the concentration of the therapeutic agent applied tothe medical device. Regardless of whether the coating is applied byspraying or by dipping or by another method or combination of methods,each layer is usually deposited on the medical device in multipleapplication steps in order to control the uniformity and the amount oftherapeutic substance and additive applied to the medical device.

Each applied layer is from about 0.1 microns to 15 microns in thickness.The total number of layers applied to the medical device is in a rangeof from about 2 to 50. The total thickness of the coating is from about2 to 200 microns.

As discussed above, spraying and dipping are particularly useful coatingtechniques for use in embodiments of the present invention. In aspraying technique, a coating solution or suspension of an embodiment ofthe present invention is prepared and then transferred to an applicationdevice for applying the coating solution or suspension to a ballooncatheter.

An application device that may be used is a paint jar attached to an airbrush, such as a Badger Model 150, supplied with a source of pressurizedair through a regulator (Norgren, 0-160 psi). When using such anapplication device, once the brush hose is attached to the source ofcompressed air downstream of the regulator, the air is applied. Thepressure is adjusted to approximately 15-25 psi and the nozzle conditionchecked by depressing the trigger.

Prior to spraying, both ends of the relaxed balloon are fastened to thefixture by two resilient retainers, i.e., alligator clips, and thedistance between the clips is adjusted so that the balloon remained in adeflated, folded, or an inflated or partially inflated, unfoldedcondition. The rotor is then energized and the spin speed adjusted tothe desired coating speed, about 40 rpm.

With the balloon rotating in a substantially horizontal plane, the spraynozzle is adjusted so that the distance from the nozzle to the balloonis about 1-4 inches. First, the coating solution is sprayedsubstantially horizontally with the brush being directed along theballoon from the distal end of the balloon to the proximal end and thenfrom the proximal end to the distal end in a sweeping motion at a speedsuch that one spray cycle occurred in about three balloon rotations. Theballoon is repeatedly sprayed with the coating solution, followed bydrying, until an effective amount of the drug is deposited on theballoon.

In one embodiment of the present invention, the balloon is inflated orpartially inflated, the coating solution is applied to the inflatedballoon, for example by spraying, and then the balloon is deflated andfolded before drying. Drying may be performed under vacuum.

It should be understood that this description of an application device,fixture, and spraying technique is exemplary only. Any other suitablespraying or other technique may be used for coating the medical device,particularly for coating the balloon of a balloon catheter or stentdelivery system or stent.

After the medical device is sprayed with the coating solution, thecoated balloon is subjected to a drying in which the solvent in thecoating solution is evaporated. This produces a coating matrix on theballoon containing the therapeutic agent. One example of a dryingtechnique is placing a coated balloon into an oven at approximately 20°C. or higher for approximately 24 hours. Any other suitable method ofdrying the coating solution may be used. The time and temperature mayvary with particular additives and therapeutic agents.

Optional Post Treatment

After depositing the drug-additive containing layer on the device ofcertain embodiments of the present invention, dimethyl sulfoxide (DMSO)or other solvent may be applied, by dip or spray or other method, to thefinished surface of the coating. DMSO readily dissolves drugs and easilypenetrates membranes and may enhance tissue absorption.

It is contemplated that the medical devices of embodiments of thepresent invention have applicability for treating blockages andocclusions of any body passageways, including, among others, thevasculature, including coronary, peripheral, and cerebral vasculature,the gastrointestinal tract, including the esophagus, stomach, smallintestine, and colon, the pulmonary airways, including the trachea,bronchi, bronchioles, the sinus, the biliary tract, the urinary tract,prostate and brain passages. They are especially suited for treatingtissue of the vasculature with, for example, a balloon catheter or astent.

Yet another embodiment of the present invention relates to a method oftreating a blood vessel. The method includes inserting a medical devicecomprising a coating into a blood vessel. The coating layer comprises atherapeutic agent and an additive. In this embodiment, the medicaldevice can be configured as having at least an expandable portion. Someexamples of such devices include balloon catheters, perfusion ballooncatheters, an infusion catheter such as distal perforated drug infusioncatheters, a perforated balloon, spaced double balloon, porous balloon,and weeping balloon, cutting balloon catheters, scoring ballooncatheters, self-expanded and balloon expanded-stents, guide catheters,guide wires, embolic protection devices, and various imaging devices.

As mentioned above, one example of a medical device that is particularlyuseful in the present invention is a coated balloon catheter. A ballooncatheter typically has a long, narrow, hollow tube tabbed with aminiature, deflated balloon. In embodiments of the present invention,the balloon is coated with a drug solution. Then, the balloon ismaneuvered through the cardiovascular system to the site of a blockage,occlusion, or other tissue requiring a therapeutic agent. Once in theproper position, the balloon is inflated and contacts the walls of theblood vessel and/or a blockage or occlusion. It is an object ofembodiments of the present invention to rapidly deliver drug to andfacilitate absorption by target tissue. It is advantageous toefficiently deliver drug to tissue in as brief a period of time aspossible while the device is deployed at the target site. Thetherapeutic agent is released into such tissue, for example the vesselwalls, in about 0.1 to 30 minutes, for example, or preferably about 0.1to 10 minutes, or more preferably about 0.2 to 2 minutes, or mostpreferably, about 0.1 to 1 minutes, of balloon inflation time pressingthe drug coating into contact with diseased vascular tissue.

Given that a therapeutically effective amount of the drug can bedelivered by embodiments of the present invention into, for example, thearterial wall, in some cases the need for a stent may be eliminated,obviating the complications of fracture and thrombosis associatedtherewith.

Should placement of a stent still be desired, a particularly preferreduse for embodiments of the present invention is to crimp a stent, suchas a bare metal stent (BMS), for example, over the drug coated balloondescribed in embodiments herein. When the balloon is inflated to deploythe stent at the site of diseased vasculature, an effective amount ofdrug is delivered into the arterial wall to prevent or decrease theseverity of restenosis or other complications. Alternatively, the stentand balloon may be coated together, or the stent may be coated and thencrimped on a balloon.

Further, the balloon catheter may be used to treat vasculartissue/disease alone or in combination with other methods for treatingthe vasculature, for example, photodynamic therapy or atherectomy.Atherectomy is a procedure to remove plaque from arteries. Specifically,atherectomy removes plaque from peripheral and coronary arteries. Themedical device used for peripheral or coronary atherectomy may be alaser catheter or a rotablator or a direct atherectomy device on the endof a catheter. The catheter is inserted into the body and advancedthrough an artery to the area of narrowing. After the atherectomy hasremoved some of the plaque, balloon angioplasty using the coated balloonof embodiments of the present invention may be performed. In addition,stenting may be performed thereafter, or simultaneous with expansion ofthe coated balloon as described above. Photodynamic therapy is aprocedure where light or irradiated energy is used to kill target cellsin a patient. A light-activated photosensitizing drug may be deliveredto specific areas of tissue by embodiments of the present invention. Atargeted light or radiation source selectively activates the drug toproduce a cytotoxic response and mediate a therapeuticanti-proliferative effect.

In some of the embodiments of drug-containing coatings and layersaccording to the present invention, the coating or layer does notinclude polymers, oils, or lipids. And, furthermore, the therapeuticagent is not encapsulated in polymer particles, micelles, or liposomes.As described above, such formulations have significant disadvantages andcan inhibit the intended efficient, rapid release and tissue penetrationof the agent, especially in the environment of diseased tissue of thevasculature.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

Other than the operating examples, or where otherwise indicated, allnumbers expressing quantities of components in a layer, reactionconditions, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless otherwise indicated to the contrary, the numericalparameters set forth in this specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present disclosure.

Preparation

The medical device and the coating layers of embodiments of the presentinvention can be made according to various methods. For example, thecoating solution can be prepared by dispersing, dissolving, diffusing,or otherwise mixing all the ingredients, such as a therapeutic agent, anadditive, and a solvent, simultaneously together. Also, the coatingsolution can be prepared by sequentially adding each component based onsolubility or any other parameters. For example, the coating solutioncan be prepared by first adding the therapeutic agent to the solvent andthen adding the additive. Alternatively, the additive can be added tothe solvent first and then the therapeutic agent can be later added. Ifthe solvent used does not sufficiently dissolve the drug, it ispreferable to first add the additive to the solvent, then the drug,since the additive will increase drug solubility in the solvent.

EXAMPLES

The following examples include embodiments of medical devices andcoating layers within the scope of the present invention. While thefollowing examples are considered to embody the present invention, theexamples should not be interpreted as limitations upon the presentinvention.

Example 1 Preparation of Coating Solutions

Formulation 1-50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 25-100 mg ascorbyl palmitate, 25-100 mg L-ascorbic acid and0.5 ml ethanol were mixed.

Formulation 2-50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (orethanol), 50-200 mg polyglyceryl-10 oleate and 0.5 ml ethanol weremixed.

Formulation 3-50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 50-200 mg octoxynol-9 and 0.5 ml ethanol were mixed.

Formulation 4-50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (orethanol), 50-200 mg p-isononylphenoxypolyglycidol and 0.5 ml ethanolwere mixed.

Formulation 5-50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 50-200 mg Tyloxapol and 0.5 ml ethanol were mixed.

Formulation 6-50-150 mg (0.05-0.16 mmole) rapamycin in 2-6 ml acetone(or ethanol), 50-150 mg L-ascorbic acid in 1 ml water or ethanol, both,then were mixed.

Formulation 7-50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone (orethanol), 50-150 mg niacinamide in 1 ml water or ethanol, were mixed.

Formulation 8-50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (orethanol), 50-200 mg nicotinic acid in 1 ml water or ethanol, were mixed.

Formulation 9-50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml ethanol (oracetone), 150 mg thiamine hydrochloride in 1 ml water, and 0.5 ml weremixed.

Formulation 10-50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone orethanol, 150 mg 2-pyrrolidone-5-carboxylic acid in 1 ml water orethanol, were mixed.

Formulation 11-50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone(or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg niacinamide in1 ml water or ethanol, and 0.5 ml ethanol were mixed.

Formulation 12-50-150 mg (0.05-0.16 mmole) rapamycin, 2-6 ml acetone (orethanol), 75 mg Octoxynol-9, 75 mg thiamine hydrochloride in 1 ml wateror ethanol, and 0.5 ml ethanol were mixed.

Formulation 13-50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone(or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg2-pyrrolidone-5-carboxylic acid in 1 ml water or ethanol, and 0.5 mlethanol were mixed.

Formulation 14-50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone(or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg nicotinic acidin 1 ml water or ethanol, and 0.5 ml ethanol were mixed.

Formulation 15 50-150 mg (0.06-0.18 mmole) paclitaxel, 2-6 ml acetone(or ethanol), 75 mg p-isononylphenoxypolyglycidol, 75 mg L-ascorbic acidin 1 ml water or ethanol, and 0.5 ml ethanol were mixed.

Formulation 16 50-150 mg (0.06-0.18 mmole) paclitaxel was dissolved in5-10 ml methylene chloride. The solution was added to 30 ml of humanserum albumin solution (5% w/v). The solution was then homogenized for 5minutes at low speed to form an emulsion. The emulsion was thensonicated at 40 kHz at 50-90% power at 0 to 5° C. for 1 to 5 min.

Formulation 17-50-150 mg (0.05-0.16 mmole) rapamycin was dissolved in5-10 ml methylene chloride and 10-30 mg p-isononylphenoxypolyglycidol.The solution was added to 30 ml of human serum albumin solution (5%w/v). The solution was then homogenized for 5 minutes at low speed toform an emulsion. The emulsion was then sonicated at 40 kHz at 50-90%power at 0 to 5° C. for 1 to 5 min.

Formulation 18-50-100 mg (0.06-0.12 mmole) paclitaxel, 1-1.6 ml acetone,1-1.6 ml ethanol, 0.4-1.0 ml water, and 50-200 mg gluconolactone weremixed.

Formulation 19-35-70 mg (0.042-0.084 mmole) paclitaxel, 0.5-1.0 mlacetone, 0.5-1.0 ml ethanol, 35-70 mg Tween 20, and 35-70 mg N-octanoylN-methylglucamine were mixed.

Formulation 20-35-70 mg (0.042-0.084 mmole) paclitaxel, 0.4-1.0 mlacetone, 0.4-1.0 ml ethanol, 0.2-0.4 ml water, 35-70 mg Tween 20, and35-70 mg sorbitol were mixed.

Formulation 21-40-80 mg (0.048-0.096 mmole) paclitaxel, 0.5-1.0 mlacetone, 0.5-1.0 ml ethanol, 40-80 mg meglumine, and 32-64 mg gensiticacid (equal molar ratio with meglumine) were mixed.

Formulation 22-35-70 mg (0.042-0.084 mmole) paclitaxel, 0.4-0.8 mlacetone, 0.4-0.8 ml ethanol, 0.25-0.50 ml water, 35-70 mg lactobionicacid, and 10-20 mg diethanolamine (equal molar ratio with lactobionicacid) were mixed.

Formulation 23-35-70 mg (0.042-0.084 mmole) paclitaxel, 0.5-1.0 mlacetone, 0.5-1.0 ml ethanol, and 70-140 mg N-octanoyl N-methylglucaminewere mixed.

Formulation 24-35-70 mg (0.042-0.084 mmole) paclitaxel, 0.4-0.8 mlacetone, 0.4-0.8 ml ethanol, 0.2-0.4 ml water, 35-70 mg meglumine, and18-36 mg lactic acid (equal molar ratio with meglumine) were mixed.

Formulation 25-50-100 mg (0.06-0.12 mmole) paclitaxel, 0.8-1.6 mlacetone, 0.8-1.6 ml ethanol, 0.4-1.0 ml water, 50-100 mg gensitic acid,and 30-60 mg diethanolamine (equal molar ratio with gensitic acid) weremixed.

Formulation 26-Comparison solution-50 mg (0.06 mmole) paclitaxel, 1 mlethanol, 0.2 ml acetone, 0.042 ml Ultravist 370 were mixed.

Formulation 27-Comparison solution-40 mg (0.048 mmole) paclitaxel, 0.5ml ethanol, 0.5 ml acetone were mixed.

Formulation 28-35-70 mg (0.042-0.084 mmole) paclitaxel, 0.5-1.0 mlacetone, 0.5-1.0 ml ethanol, 35-70 mg Triton X-100, and 35-70 mgN-heptanoyl N-methylglucamine were mixed.

Example 2

5 PTCA balloon catheters (3 mm in diameter and 20 mm in length) werefolded with three wings under vacuum. The folded balloon under vacuumwas sprayed or dipped in a formulation (1-17) in example 1. The foldedballoon was then dried, sprayed or dipped again, dried again, andsprayed or dipped again until sufficient amount of drug on the balloon(3 microgram per square mm) was obtained. The coated folded balloon wasthen rewrapped and sterilized for animal testing.

Example 3

5 PTCA balloon catheters (3 mm in diameter and 20 mm in length) wasfolded with three wings under vacuum. The folded balloon under vacuumwas sprayed or dipped in a formulation (1-5) in example 1. The foldedballoon was then dried, sprayed or dipped again in a formulation (6-10),dried, and sprayed or dipped again until sufficient amount of drug onthe balloon (3 microgram per square mm) was obtained. The coated foldedballoon was then rewrapped and sterilized for animal testing.

Example 4

5 PTCA balloon catheters crimped with bare metal coronary stent (3 mm indiameter and 20 mm in length) were sprayed or dipped in a formulation(1-5) in example 1. The stent delivery system was then dried, sprayed ordipped again in a formulation (6-10), dried and sprayed or dipped againuntil sufficient amount of drug on the stent and balloon (3 microgramper square mm) is obtained. The coated folded stent delivery system wasthen sterilized for animal testing.

Example 5

Drug coated balloon catheters and uncoated balloon catheters (ascontrol) were inserted into coronary arteries in pigs. The balloon wasover dilated (1:1.2), and the inflated balloon was held in the vesselfor 60 seconds to release drug and additive, then deflated and withdrawfrom the pig. The animals were angiographed after 3 days, 31 days, 3months, 6 months, 9 months and 12 months. The amount of drug in theartery tissues of the sacrificed animal was measured after 60 minutes, 3days, 31 days, 3 months, 6 months, 9 months and 12 months.

Example 6

5 coronary stents (3 mm in diameter and 18 mm in length) were spray ordip coated with the formulation (1-17) in example 1. The stents werethen dried, sprayed or dipped again, and dried again until a sufficientamount of drug on the stent (3 microgram per square mm) is obtained. Thecoated stent was then crimped on PTCA balloon catheters (3 mm indiameters and 20 mm in length). The coated stents with balloon catheterswere then sterilized for animal testing.

Example 7

The drug coated stent and uncoated stent (as control) were inserted intocoronary arteries in pigs, then the balloon was over dilated (1:1.2).The stent was implanted and drug and additive released, and the balloonwas deflated and withdrawn from the pig. The animals were thenangiographed after 5, 30, 60 minutes, 3 days, 31 days, 3 months, 6months, 9 months and 12 months. The amount of drug in the artery tissuesof the sacrificed animal was measured 60 minutes, 1 day, 3 days, 31days, 3 months, 6 months, 9 months and 12 months.

Example 8

5 PTCA balloon catheters were sprayed or dipped in the formulation(1-17) in example 1, dried, and sprayed or dipped and dried again untilsufficient amount of drug on balloon is obtained (3 microgram per squaremm) was obtained. A bare metal coronary stent (3 mm in diameter and 20mm in length) was crimped on each coated balloon. The coated balloonswith crimped bare metal stents were then wrapped and sterilized foranimal test.

Example 9

5 PTCA balloon catheters were sprayed or dipped in a formulation (1-5)in example 1, dried, and sprayed or dipped again in a formulation(6-10). Balloons were then dried and sprayed or dipped again untilsufficient amount of drug on the balloon (3 microgram per square mm) wasobtained. A bare metal coronary stent (3 mm in diameter and 20 mm inlength) was crimped on each coated balloon. The coated balloons withcrimped bare metal stents were then wrapped and sterilized for animaltest.

Example 10

The drug coated balloon-expandable bare metal stent of Examples 8 and 9and plain balloon-expandable bare metal stent (as control) were insertedinto coronary arteries in pigs, and the balloon is over dilated (1:1.2).Stent is implanted, and the balloon was held inflated for 60 seconds torelease drug and additive, and the balloon was deflated and withdrawfrom the pig. The animals were then angiographed after 5, 30, 60minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months.The amount of drug in the artery tissues of the sacrificed animal ismeasured after 60 minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9months and 12 months.

Example 11

150 mg (0.18 mmole) paclitaxel, 5 ml acetone (or ethylacetate or methylethyl ketone), 150 mg acetic anhydride or maleic anhydride or diglycolicanhydride and 0.5 ml ethanol were mixed, then stirred until a solutionwas obtained. 5 PTCA balloon catheters were sprayed or dipped in thesolution, dried, and sprayed or dipped again until sufficient amount ofdrug on the balloon (3 microgram per square mm) is obtained. The coatedballoon was then treated under high pH (range pH 8-11.5) conditions tohydrolyze the anhydride. This can be confirmed by IR method. Thehydrophilicity of the coating was now increased. The coated balloonswere then sterilized for animal test.

Example 12

The drug coated balloon catheters and uncoated balloon catheters (ascontrol) were inserted via a bronchoscope into the pulmonary airway inpigs. The balloon was dilated, and the inflated balloon was heldexpanded in the lumen for 60 seconds to release drug and additive. Theballoon was deflated and withdrawn from the pig. The animals were thenexamined bronchoscopically and tissues samples were taken for pathologyand quantification of drug uptake after 3 days, 31 days, 3 months, 6months, 9 months and 12 months.

Example 13

The uncoated stent delivery catheters were inserted into the vascularlumen in pigs. The balloon was dilated, the stent was deployed and thedeflated balloon was the withdrawn. The pharmaceutical formulation 1-15of example 1 (10-100 ml) was injected (about 5-15 mg drug per pig) atthe site of stent implantation. The drug was then absorbed by injuriedtissue. The animals were then examined and tissues samples were takenfor pathology.

Example 14

The diseased tissue (breast cancer or prostate or atheroma or stenosis)was removed surgically from a human body. The pharmaceutical formulation1-15 of example 1 (10-100 ml) was then injected into or onto thesurgical cavities created by the surgical intervention (about 5-20 mgdrug). The local drug delivery included injection by long needle, guidecatheters, introducer shealth, drug infusion tube and other drugdelivery catheters. The drug was then absorbed by tissue at the targetsite.

Example 15

6 PTCA balloon catheters (3.5 and 3.0 mm in diameter and 20 mm inlength) were inflated at 1-3 atm. The inflated balloon was loaded with aformulation 18-28 in example 1. A sufficient amount of drug on theballoon (3 microgram per square mm) was obtained. The inflated balloonwas folded, and then dried. The coated folded balloon was then rewrappedand sterilized for animal testing.

The coated PTCA balloon catheter was inserted into a target site in thecoronary vasculature (LAD, LCX and RCA) of a 25-45 pound pig. Theballoon was inflated to about 12 atm. The overstretch ratio (the ratioof balloon diameter to vessel diameter) was about 1.15-1.20. The drugdelivered into the target tissue during 30-60 seconds of inflation. Theballoon catheter was then deflated and was withdrawn from animal body.The target blood vessel was harvested 0.25-24 hours after the procedure.The drug content in the target tissue and the residual drug remaining onthe balloon were analyzed by tissue extraction and HPLC.

In some of these animal studies, a stent was crimped on the drug coatedballoon catheters prior to deployment. In chronic animal tests,angiography was performed before and after all interventions and at28-35 days after the procedure. Luminal diameters were measured and latelumen loss was calculated. Late lumen loss is the difference between theminimal lumen diameter measured after a period of follow-up time(usually weeks to months after an intervention, such as angioplasty andstent placement in the case of this example) and the minimal lumendiameter measured immediately after the intervention. Restenosis may bequantified by the diameter stenosis, which is the difference between themean lumen diameters at follow-up and immediately after the proceduredivided by the mean lumen diameter immediately after the procedure. Theanimal test results for Formulations 18-28 are reported below. All datais an average of five or six experimental data points.

The drug content of the formulation 18 on the 3.5 mm balloon catheterswas 3.26 μg/mm². After the procedure, the residual drug on the balloonwas 15.92 μg, or 2.3% of the total drug loaded on the balloon. The drugcontent in tissue harvested 15-30 minutes after the procedure was 64.79μg, or 9.2% of the total drug content originally loaded on the balloon.When an 18 mm stent was deployed by the coated balloon, the residualdrug on the balloon was 31.96 μg, or 4.5% of drug load, and the drugcontent in tissue harvested 15-30 minutes after the procedure was 96.49μg, or 13.7% of drug load. The stretch ratio is 1.3 in the procedure.The late lumen loss after 28-35 days was 0.10 (sd 0.2) mm. The diameterstenosis is 3.3%.

The drug content of the formulation 19 on the 3.5 mm balloon catheterswas 3.08 μg/mm². After the procedure, the residual drug on the balloonwas 80.58 μg, or 11.4% of the total drug load. The drug content intissue harvested 15-30 minutes after the procedure was 42.23 μg, or 6.0%of the total drug load. After 28-35 days late lumen loss was 0.30 (sd0.23) mm. The diameter stenosis was 5.4%.

The drug content of formulation 20 on the 3.5 mm balloon catheters was3.61 μg/mm². After the procedure, the residual drug on the balloon was174.24 μg, or 24.7% of the total drug load. The drug content in tissueharvested 15-30 minutes after the procedure was 83.83 μg, or 11.9% ofthe total drug load. When deployed with a pre-crimped 18 mm stent, theresidual drug on the balloon is 114.53 μg, or 16.1% of the total drugload, and the drug content in tissue harvested 15-30 minutes postprocedure was 147.95 μg, or 18.1% of the total drug load. The stretchratio was 1.3 in the procedure. The late lumen loss after 28-35 days was0.10 (sd 0.1) mm. The diameter stenosis was 3.4%.

The drug content of formulation 21 on the 3.5 mm balloon catheters was4.71 μg/mm². After the procedure, the residual drug on the balloon was44.39 μg, or 6.3% of the total drug load. The drug content in the tissueharvested 15-30 minutes after the procedure was 77.87 μg, or 11.0% ofthe total drug load. After 28-35 days late lumen loss was 0.23 (sd 0.44)mm. The diameter stenosis was 7.3%.

The drug content of the formulation 22 on the 3.5 mm balloon catheterswas 3.85 μg/mm². After the procedure, residual drug on the balloon was24.59 μg, or 3.5% of the total drug load. The drug content in tissueharvested 15-30 minutes after the procedure was 37.97 μg, or 5.4% of thetotal drug load. After 28-35 days late lumen loss was 0.33(sd 0.14) mm.The diameter stenosis was 6.7%.

The drug content of formulation 23 on the 3.5 mm balloon catheters was3.75 μg/mm². After the procedure, residual drug on the balloon was 0.82μg, or 0.1% of the total drug load. The drug content in tissue harvested60 minutes after the procedure was 45.23 μg, or 5.5% of the total drugload. After 28-35 days late lumen loss was 0.49 (sd 0.26) mm. Thediameter stenosis was 11.3%.

The drug content of formulation 24 on the 3.5 mm balloon catheters was3.35 μg/mm². After the procedure, the residual drug on the balloon was62.07 μg, or 7.5% of the total drug load. The drug content in tissueharvested 60 minutes after the procedure was 40.55 μg, or 4.9% of thetotal drug load. After 28-35 days late lumen loss was 0.47 (sd 0.33) mm.The diameter stenosis was 9.9%.

The drug content of the formulation 25 on the 3.5 mm balloon catheterswas 3.41 μg/mm². After the procedure, residual drug on the balloon was50.0 μg, or 6.0% of the total drug load. The drug content in tissueharvested 60 minutes post procedure was 26.72 μg, or 3.2% of the totaldrug load. After 28-35 days late lumen loss was 0.36 (sd 0.41) mm. Thediameter stenosis was 9.3%.

The drug content of formulation 28 on the 3.5 mm balloon catheters was3.10 μg/mm². After the procedure, residual drug on the balloon was 1.9%of the total drug load. The drug content in tissue harvested 2 hoursafter the procedure was 34.17 μg, or 5.0% of the total drug load. Intissue harvested 24 hours after the procedure, the drug content intissue was 28.92 μg, or 4.2% of the total drug load.

The drug content of control formulation (uncoated balloon) on the 3.5 mmballoon catheters was 0.0 μg/mm². After the procedure, residual drug onthe balloon was 0% of the total drug load. The drug content in tissueharvested 15 minutes after the procedure was 0 μg. In tissue harvested24 hours after the procedure, the drug content in tissue was 0 μg. after28-35 days late lumen loss was 0.67 (sd 0.27) mm. The diameter stenosisis 20.8%. In the second repeat experiment, the stretch ratio was 1.3.The late lumen loss was 1.1 (sd 0.1). The diameter stenosis was 37.5%.

The drug content of the comparison formulation 26 on the 3.5 mm ballooncatheters was 3.21 μg/mm². After the procedure, residual drug on theballoon was 13.52 μg, or 1.9% of the total drug load. The drug contentin the tissue was 28.32 μg, or 4.0% of the total drug load. When theballoon was deployed with a pre-crimped 18 mm stent, residual drug onthe balloon was 26.45 μg, or 3.7% of the total drug load. The drugcontent in tissue was 113.79 μg, or 16.1% of drug load. After 28-35days, late lumen loss was 0.27 (sd 0.15) mm. The diameter stenosis was7.1%.

The drug content of the formulation 27 (without additive) on the 3.5 mmballoon catheters was 4.22 μg/mm². After the procedure, residual drug onthe balloon was 321.97 μg, or 45.6% of the total drug load. The drugcontent in the tissue was 12.83 μg, or 1.8% of the total drug load.

Surprisingly, the concentration of drug absorbed by porcine coronaryartery tissue after deployment of balloons coated with formulations18-25 and 28 according to embodiments of the present invention washigher than that delivered by balloons coated with the comparisonformulation 26 and higher than those coated with drug alone, formulation27. The late lumen loss after 28-35 days follow up was less than thecontrol (uncoated balloon).

Example 16

6 PTCA balloon catheters (3.5 and 3.0 mm in diameter and 20 mm inlength) were inflated at 1-3 atm. The inflated balloon was loaded with aformulation 18-25, and 28 in example 1. A sufficient amount (3 μg/mm²)of drug on the balloon surface was obtained. The inflated balloon wasdried. The drug coated balloon was then loaded with a top coat. The topcoating formulation in acetone or ethanol was chosen from gentisic acid,methyl paraben, acetic acid, Tween 20, vanillin and aspirin. The coatedfolded balloon was dried, then rewrapped and sterilized for animaltesting.

A floating experiment was designed to test how much drug is lost duringballoon catheter insertion and transit to the target site prior toinflation. A control balloon catheter was coated with formulation 18.Top-coated catheters also were prepared having a top coating of propylparaben. For top-coated catheters, the balloon catheter was coated withformulation 18, then dried, 25-50 mg propyl paraben (about 50% ofpaclitaxel by weight) in acetone was coated over the formulation 18coating. Each of the control and top-coated balloon catheters wasinserted in pig arteries. The floating time in pig arterial vasculaturewas 1 minute. The drug, additive and top coating were released. Thecatheter was then withdrawn. The residual drug on the balloon catheterswas analyzed by HPLC. The residual drug content of the control ballooncatheters was 53% of the total drug loading. The residual drug contentof the top-coated balloon catheter was 88%. The top coat reduced drugloss in the vasculature during conditions that simulate transit of thedevice to a site of therapeutic intervention. The same animal tests wereperformed as in Example 15 with formulation 18 first coated on theballoon, and propyl paraben as a top coating layer overlying the firstcoating layer. The drug content on the 3.5 mm balloon catheter was 3.39μg/mm². After the procedure, residual drug on the balloon was 64.5 μg,or 8.6% of the total drug load. The drug content in the tissue was 28.42μg, or 4% of the total drug load.

Example 17

6 PTCA balloon components (3.5 and 3.0 mm in diameter and 20 mm inlength) were loaded with formulation 18 provided in Example 1. Asufficient amount of drug (3 μg/mm²) was obtained on the balloonsurface. The balloon was dried.

A formulation for a top coating layer was then prepared. The formulationof the top coating layer was paclitaxel, and one additive chosen fromTween 20, Tween 80, polypropylene glycol-425 (PPG-425), and polypropylglycol-1000 (PPG-1000), in acetone. The balloon surface of the controlcatheters was only loaded with formulation 18. 25-50 mg of the topcoating formulation (about 50% of paclitaxel by weight) in acetone wascoated over the formulation 18 coating layer on the other balloonsurfaces. The coated balloons were dried for drug releasing testing invitro.

The releasing experiment was designed to test how much drug is lostduring balloon inflation. Each of the coated balloons were inflated to12 atm. in 1% BSA solution at 37° C. for 2 minutes. The drug, additiveand top coating were released. The residual drug on the ballooncatheters was analyzed by HPLC. The residual drug content of the controlballoon catheter was 34% of the total drug loading. The residual drugcontent of the balloon catheter that included a top coating layer withTween 20, Tween 80, polypropylene glycol-425 (PPG-425) or polypropylglycol-1000 (PPG-1000) was 47%, 56%, 71% and 81%, respectively. Thus,the top coating layer reduced drug loss in the tests in vitro duringinflation of the balloon components.

1. A method for treating a blood vessel, the method comprising:inserting a balloon catheter to a target site in the blood vessel, theballoon catheter comprising a balloon and a coating layer overlyingexternal surfaces of the balloon, wherein: the coating layer comprises awater-soluble first additive, a water-soluble second additive, and aninitial drug load of a hydrophobic therapeutic agent; the coating layerdoes not include an iodine covalent-bonded contrast agent, a dye, anoil, or a lipid; the hydrophobic therapeutic agent is selected from thegroup consisting of paclitaxel, paclitaxel analogues, rapamycin,rapamycin analogues, and combinations thereof; the hydrophobictherapeutic agent is not enclosed in micelles or liposomes and is notencapsulated in polymer particles; the water-soluble first additive is asurfactant selected from the group consisting of PEG sorbitanmonolaurates, PEG sorbitan monooleates, and combinations thereof; thewater-soluble second additive is a chemical compound having at leastfour hydroxyl groups, the chemical compound being selected from thegroup consisting of sorbitol, sorbitan, xylitol, gluconolactone, andcombinations thereof,  whereby the combination of the water-solublefirst additive and the water-soluble second additive promotes rapidrelease of the hydrophobic therapeutic agent from the balloon at thetarget site during an inflation period; inflating the balloon until thecoating layer contacts walls of the blood vessel at the target site;deflating the balloon after the inflation period, wherein the inflationperiod is from 0.1 minutes to 10 minutes; and withdrawing the ballooncatheter from the blood vessel, the balloon having thereon a residualdrug amount after the withdrawing.
 2. The method of claim 1, wherein theratio by weight of the therapeutic agent in the coating layer to thetotal weight of the first and second additives in the coating layer isfrom about 0.5 to
 3. 3. The method of claim 1, wherein the initial drugload is from 1 μg to 20 μg of the hydrophobic therapeutic agent persquare millimeter of the balloon.
 4. The method of claim 1, wherein: theinitial drug load is from 2 μg to 6 μg of the hydrophobic therapeuticagent per square millimeter of the balloon; and the residual drug amountis 24.7% or less of the initial drug load.
 5. The method of claim 1,wherein: the water-soluble first additive is selected from the groupconsisting of PEG (20) sorbitan monolaurate, PEG (20) sorbitanmonooleate, and combinations thereof.
 6. The method of claim 1, wherein:the water-soluble first additive is selected from the group consistingof PEG (20) sorbitan monolaurate, PEG (20) sorbitan monooleate, andcombinations thereof; and the water-soluble second additive is selectedfrom the group consisting of sorbitol, gluconolactone, and combinationsthereof.
 7. The method of claim 1, wherein: the water-soluble firstadditive is PEG (20) sorbitan monolaurate or PEG (20) sorbitanmonooleate; and the water-soluble second additive is selected from thegroup consisting of sorbitol, xylitol, gluconolactone, and combinationsthereof.
 8. The method of claim 1, wherein: the coating layer consistsessentially of the therapeutic agent, the first additive, and the secondadditive; the water-soluble first additive is PEG (20) sorbitanmonolaurate or PEG (20) sorbitan monooleate; and the water-solublesecond additive is sorbitol.
 9. The method of claim 1, wherein: thecoating layer consists essentially of the therapeutic agent, the firstadditive, and the second additive; the water-soluble first additive isPEG (20) sorbitan monolaurate or PEG (20) sorbitan monooleate; and thewater-soluble second additive is gluconolactone.
 10. The method of claim1, wherein: the hydrophobic therapeutic agent is paclitaxel; thewater-soluble first additive is PEG (20) sorbitan monolaurate; thewater-soluble second additive is sorbitol; the initial drug load is from2 μg to 6 μg of the hydrophobic therapeutic agent per square millimeterof the balloon; and the residual drug amount is 24.7% or less of theinitial drug load.
 11. The method of claim 10, wherein the ratio byweight of the hydrophobic therapeutic agent in the coating layer to thetotal weight of the water-soluble first and second additives in thecoating layer is from about 0.1 to
 5. 12. The method of claim 10,wherein: the coating layer consists essentially of paclitaxel, PEG (20)sorbitan monolaurate, and sorbitol; and the ratio by weight ofpaclitaxel in the coating layer to the total weight of PEG (20) sorbitanmonolaurate and sorbitol in the coating layer is from about 0.5 to 3.13. The method of claim 10, wherein: the coating layer consistsessentially of paclitaxel, PEG (20) sorbitan monooleate, and sorbitol;and the ratio by weight of paclitaxel in the coating layer to the totalweight of PEG (20) sorbitan monooleate and sorbitol in the coating layeris from about 0.5 to
 3. 14. A method for treating a blood vessel, themethod comprising: inserting a balloon catheter to a target site in theblood vessel, the balloon catheter comprising a balloon and a coatinglayer overlying external surfaces of the balloon, wherein: the coatinglayer comprises a water-soluble first additive, a water-soluble secondadditive, and a hydrophobic therapeutic agent with an initial drug loadof from 2 μg to 6 μg of the hydrophobic therapeutic agent per squaremillimeter of the balloon; the coating layer does not include an iodinecovalent-bonded contrast agent, a dye, an oil, or a lipid; thehydrophobic therapeutic agent is selected from the group consisting ofpaclitaxel, paclitaxel analogues, rapamycin, rapamycin analogues, andcombinations thereof; the hydrophobic therapeutic agent is not enclosedin micelles or liposomes and is not encapsulated in polymer particles;the water-soluble first additive is a surfactant selected from the groupconsisting of PEG (20) sorbitan monolaurate and PEG (20) sorbitanmonooleate, and combinations thereof; the water-soluble second additiveis a chemical compound having at least four hydroxyl groups, thechemical compound being selected from the group consisting of sorbitol,xylitol, gluconolactone, lactobionic acid, and combinations thereof; andthe ratio by weight of the hydrophobic therapeutic agent in the coatinglayer to the total weight of the water-soluble first and secondadditives in the coating layer is from about 0.1 to 5,  whereby thecombination of the water-soluble first additive and the water-solublesecond additive promotes rapid release of the hydrophobic therapeuticagent from the balloon at the target site during an inflation period;inflating the balloon until the coating layer contacts walls of theblood vessel at the target site; deflating the balloon after theinflation period, wherein the inflation period is from 0.1 minutes to 10minutes; and withdrawing the balloon catheter from the blood vessel, theballoon having thereon a residual drug amount of less than 24.7% of theinitial drug load after the withdrawing.
 15. The method of claim 14,wherein: the water-soluble first additive is PEG (20) sorbitanmonolaurate; and the water-soluble second additive is gluconolactone.16. The method of claim 14, wherein: the water-soluble first additive isPEG (20) sorbitan monolaurate; and the water-soluble second additive issorbitol or xylitol.
 17. The method of claim 14, wherein: thewater-soluble first additive is PEG (20) sorbitan monolaurate; and thewater-soluble second additive is lactobionic acid.
 18. The method ofclaim 14, wherein: the water-soluble first additive is PEG (20) sorbitanmonooleate; and the water-soluble second additive is gluconolactone. 19.The method of claim 14, wherein: the water-soluble first additive is PEG(20) sorbitan monooleate; and the water-soluble second additive issorbitol or xylitol.
 20. A method for treating a blood vessel, themethod comprising: inserting a balloon catheter to a target site in theblood vessel, the balloon catheter comprising a balloon and a coatinglayer overlying external surfaces of the balloon, wherein: the coatinglayer comprises a water-soluble first additive, a water-soluble secondadditive, and an initial drug load of a hydrophobic therapeutic agent;the coating layer does not include an iodine covalent-bonded contrastagent, a dye, an oil, or a lipid; the hydrophobic therapeutic agent isselected from the group consisting of paclitaxel, paclitaxel analogues,rapamycin, rapamycin analogues, and combinations thereof; thehydrophobic therapeutic agent is not enclosed in micelles or liposomesand is not encapsulated in polymer particles; the water-soluble firstadditive is a surfactant selected from the group consisting of PEG (20)sorbitan monolaurate, PEG (20) sorbitan monooleate, and combinationsthereof; the water-soluble second additive is a chemical compound havingat least four hydroxyl groups, the chemical compound being selected fromthe group consisting of sorbitol, xylitol, gluconolactone, lactobionicacid, and combinations thereof,  whereby the combination of thewater-soluble first additive and the water-soluble second additivepromotes rapid release of the hydrophobic therapeutic agent from theballoon at the target site during an inflation period; inflating theballoon until the coating layer contacts walls of the blood vessel atthe target site; deflating the balloon after the inflation period,wherein the inflation period is from 0.1 minutes to 2 minutes; andwithdrawing the balloon catheter from the blood vessel, the balloonhaving thereon a residual drug amount after the withdrawing.
 21. Themethod of claim 20, wherein: the initial drug load is from 2 μg to 6 μgof the hydrophobic therapeutic agent per square millimeter of theballoon; and the residual drug amount is 24.7% or less of the initialdrug load.
 22. The method of claim 21, wherein the water-soluble firstadditive is PEG (20) sorbitan monolaurate.
 23. The method of claim 21,wherein the water-soluble second additive is sorbitol or gluconolactone.24. The method of claim 21, wherein: the coating layer consistsessentially of paclitaxel, PEG (20) sorbitan monolaurate, and sorbitol;and the ratio by weight of paclitaxel in the coating layer to the totalweight of PEG (20) sorbitan monolaurate and sorbitol in the coatinglayer is from about 0.1 to
 5. 25. The method of claim 21, wherein: thecoating layer consists essentially of paclitaxel, PEG (20) sorbitanmonooleate, and sorbitol; and the ratio by weight of paclitaxel in thecoating layer to the total weight of PEG (20) sorbitan monooleate andsorbitol in the coating layer is from about 0.1 to
 5. 26. A method fortreating a body passage, the method comprising: removing plaque from atarget site in the body passage by one of a debulking catheter, a laseratherectomy, a directing atherectomy, or a rotational atherectomy;inserting a balloon catheter to the target site in the body passage, theballoon catheter comprising a balloon and a coating layer overlyingexternal surfaces of the balloon, wherein: the coating layer comprises awater-soluble first additive, a water-soluble second additive, and aninitial drug load of a hydrophobic therapeutic agent; the coating layerdoes not include an iodine covalent-bonded contrast agent, a dye, anoil, or a lipid; the hydrophobic therapeutic agent is selected from thegroup consisting of paclitaxel, paclitaxel analogues, rapamycin,rapamycin analogues, and combinations thereof; the hydrophobictherapeutic agent is not enclosed in micelles or liposomes and is notencapsulated in polymer particles; the water-soluble first additive is asurfactant selected from the group consisting of PEG sorbitanmonolaurates, PEG sorbitan monooleates, and combinations thereof; thewater-soluble second additive is a chemical compound having at leastfour hydroxyl groups, the chemical compound being selected from thegroup consisting of sorbitol, sorbitan, xylitol, gluconolactone, andcombinations thereof,  whereby the combination of the water-solublefirst additive and the water-soluble second additive promotes rapidrelease of the hydrophobic therapeutic agent from the balloon at thetarget site during an inflation period; inflating the balloon until thecoating layer contacts walls of the body passage at the target site;deflating the balloon after the inflation period, wherein the inflationperiod is from 0.1 minutes to 10 minutes; and withdrawing the ballooncatheter from the body passage, the balloon having thereon a residualdrug amount after the withdrawing.
 27. The method of claim 26, wherein:the coating layer consists essentially of the therapeutic agent, thefirst additive, and the second additive; the hydrophobic therapeuticagent is paclitaxel; the water-soluble first additive is PEG (20)sorbitan monolaurate or PEG (20) sorbitan monooleate; and thewater-soluble second additive is sorbitol or gluconolactone.
 28. Themethod of claim 27, wherein: the initial drug load is from 2 μg to 6 μgof the hydrophobic therapeutic agent per square millimeter of theballoon; and the residual drug amount is 24.7% or less of the initialdrug load.
 29. The method of claim 26, wherein the ratio by weight ofthe therapeutic agent in the coating layer to the total weight of thefirst and second additives in the coating layer is from about 0.5 to 3.